DSpace at VNU: Synthesis and molecular structures of dibenzo(perhydrotriazino)aza-14- crown-4 ethers

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol 47, No 5, pp 766−770 © Pleiades Publishing, Ltd., 2011 Original 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 Organicheskoi Khimii, 2011, Vol 47, No 5, pp 760−763 Synthesis and Molecular Structures of Dibenzo(perhydrotriazino)aza-14-crown-4 Ethers Chyong Khong Khieua,A T Soldatenkova, Le Tuan An’b, A N Levova, A F Smol’yakovc, V N Khrustalevc, and M Yu Antipinc aRussian University of Peoples’ Friendship, Moscow, 117198 Russia e-mail: soldatenkovat@yandex.ru bVietnam State University, Hanoi University of Sciences, Vietnam cNesmeyanov Institute of Organoelemental 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 DOI: 10.1134/S1070428011050174 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 CHO OHC R2 + O O 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-14crown-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 1H NMR spectrum of this azacrown, highly symmetric with respect to similar protons, two protons H1 and H21 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 H22 and H24 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 NHR1 H2N O IIа_IId I R2 + NH4OAc N 21 25 N H O R1 22 24 HN 19 18 15 O O 10 20 12 _ 17 16 13 IIIа IIId 766 767 SYNTHESIS AND MOLECULAR STRUCTURES OF DIBENZO(PERHYDROTRIAZINO)AZA- Parameters of hydrogen bonds in complex (IIIa)·CHCl3a N22–H22N⋯S1#1 N24–H24N⋯Cl3 0.92 0.90 2.45 2.69 3.348(2) 3.574(2) Angle D–H⋯A, deg 166 169 N24–H24N⋯Cl3' 0.90 2.80 3.698(2) 172 N25–H25N⋯O8 0.90 2.33 2.938(2) 124 N25–H25N⋯O14 0.90 2.52 3.046(2) 118 C24–H24A⋯S1 1.00 2.47 3.447(2) 165 C24–H24B⋯S1 1.00 2.46 3.447(2) 170 Parameters a Fig Molecular structure of complex (IIIa)·CHCl3 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 CHCl3 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 N25⋯O8⋯O11⋯O14, equals 4.04 Ǻ The conformation of the polyether fragment (C7O8C9C10O11C12C13O14C15) is t -g(–)-t-t-g(+)-t (t is trans, ±180°; g is gauche, ±60°) The molecule of compound IIIa possesses an idealized symmetry Cs(m) that however in the crystal is slightly distorted due to the formation of two unsymmetrical intramolecular hydrogen bonds N25–H25⋯O8 (see the table and Fig 1) [N⋯O 2.938(2), H⋯O 2.33 Ǻ, angle NH⋯O 124°] and N25–H25⋯O14 [N⋯O 3.046(2), H⋯O 2.52 Ǻ, angle NH⋯O 118°] Owing to the intramolecular hydrogen bonds the donor atoms of the azacrown ring N25, O8, O11, O14 not lie in the same plane (mean-square deviation 0.112 Ǻ) Atoms N22 and N24 have the planar-trigonal configuration (the sum of bond angles is 357.0 and 357.1° D–H, Å H⋯A, Å D⋯A, Å D is proton-donor, A is proton-acceptor Symmetric transformation for the equivalent atom: 1#1 –x + 1/2, –y + 1/2, –z + respectively) which slightly tends to pyramidal because of the intermolecular hydrogen bonds (see below) The atom N25 assumes the pyramidal configuration The sum of bond angles at these atoms equals 329.2° The triazine ring in the molecule IIIa has the conformation of a flattened boat (deviations of atoms C23 and N25 from the mean-square plane of the other atoms of the ring are 0.136 and 0.653 Ǻ respectively) Compound IIIa is a diastereomer with two asymmetric centers (C1 and C21) 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 46.5° Compound IIIa and the chloroform molecule are bound into a complex through an intermolecular hydrogen bonds (see the table and Fig 1) N24–H24N⋯Cl3 and C24–H24A⋯S1 (N24–H24N⋯Cl3’ and C24–H24B⋯S1 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 N22–H22N⋯S1 (–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 JOURNAL OF ORGANIC CHEMISTRY Vol 47 No 2011 768 CHYONG KHONG KHIEU et al yield (63%) Its 1H 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 H24 was observed The signals of the other three protons of the triazine ring H25 (t, J 12.0 Hz), H1 (d.d, J 12.0 and 1.3 Hz), and H21 (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, 3Jtrans 14.1 and 2J 1.2 Hz), 5.00 (d.d, 3Jcis 9.0 and 2J 1.2 Hz), 5.24 (d.d, J 12.3 and 5.0 Hz) and 5.83 (m) ppm Fig Centrosymmetric dimeric associates of complex (IIIa)·CHCl3 The hydrogen bonds are shown by dashed lines The alternative positions of the atoms of the disordered chloroform molecule are not shown 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 1H 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 Fig Crystal packing of dimeric associates of complex (IIIa)·CHCl3 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 1H NMR spectrum the protons of the methyl group were observed as a singlet at 3.03 ppm Also the signals are pronounced of protons H25, H1, and H21: 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 C1H–N25H–C21H The introducing of a methyl group into the thiourea fragment resulted in a considerable shift of the proton signal NH24 (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 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 DMSO-d6 (compounds IIIa, IIIc, IIId) and CDCl3 (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 JOURNAL OF ORGANIC CHEMISTRY Vol 47 No 2011 SYNTHESIS AND MOLECULAR STRUCTURES OF DIBENZO(PERHYDROTRIAZINO)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 C20H22Cl3N3S, M 490.82, monoclinic crystal system, space group C2/c, at 100 K a 28.5499(12), b 7.4853(3), c 21.6111(3) Å, β 102.657(1)°, V 4506.2(3) Å3, Z 8, dcalc 1.447 g/cm3, F(000) 2032, μ 0.527 mm–1, 2θmax 56° Number of measured reflections 23770, number of independent reflections 5942, number of reflections with I > 2σ(I) 4755 Number of refined parameters 289, R1 [I > 2σ(I)] 0.044, wR2 (for all data) 0.120 GOF 1.001 The parameters of the unit cell and the intensities of reflections were measured on an automatic three-circle diffractometer Bruker APEX-II CCD (MOKα-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 [Uiso(H) = 1.2Ueq(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 [Uiso(H) = 1.2Uequiv(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)·CHCl3 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 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 , 11 , - Tr i o x a - 2 , , - t r i a z a t e t r a c y c lo[19.3.1.0 2,7 15,20 ]pentacosa-2,4,6,15(20),16,18hexaene-23-thioH (IIIa) Yield 2.70 g (73%), mp 188– 190°C IR spectrum, ν, cm–1: 3397, 3322 and 3195 (NH), 769 1059 (SH) 1H NMR spectrum, δ, ppm: 3.93 m, 4.00 m, 4.16 m (3H, 4H, 2H resp., OCH2CH2O and H25), 5.28 d.d (2H, H1,21, J 11.6, 1.2 Hz), 6.90 t (2H, H4,18, J 7.6 Hz), 6.94 d (2H, H6,16, J 8.0 Hz), 7.25 d (2H, H3,19, J 7.6 Hz) 7.31 t (2H, H5,17, J 8.0 Hz), 7.94 d (2H, H22,24, J 1.2 Hz) Mass spectrum, m/z (Irel, %): 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 11.22 C19H21N3O3S Calculated, %: C 61.44; H 5.70; N 11.13 M 371.45 23-Methyl-8,11,14-trioxa-22,24,25-triazatetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),16,18hexaene-23-thione (IIIb) Yield 2.70 g (73%), mp 184–186°C IR spectrum, ν, cm–1: 3312, 3184 (N–H); 1261, 1076, 1055 (C=S) 1H NMR spectrum, δ, ppm: 3.03 s (3H, NMe), 3.95–4.22 m (8H, OCH2CH2O), 4.53 t (1H, H25, J 12.6, J 12.4 Hz), 5.27 d.d (1H, H1, J 12.4, J 2.2 Hz), 5.41 d (1H, H21, J 12.6 Hz), 6.78 br.s (1H, H24), 6.84 d (2H, H6,16, J 8.2 Hz), 6.90 t.t, 6.93 t.t (1H each, H4,18, J 8.2, J 1.5 Hz), 7.20 and 7.24 d.d (1H each, H3,19, J 7.5, J 1.5 Hz), 7.29 and 7.31 t.t (1H each, H5,17, J 8.2, J 1.5 Hz) Mass spectrum, m/z (Irel, %): 385 [M]+ (8), 356 (2) [M – NCH3]+, 352 (5), 311 (14), 297 (6) [M – CH3NCSNH2]+, 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 10.73 C20H23N3O3S Calculated, %: C 62.34; H 5.97; N 10.91 M 385.48 23-Allyl-8,11,14-trioxa-22,24,25-triazatetracyclo[19.3.1.0 2,7.0 15,20]pentacosa-2,4,6,15(20),16,18hexaene-23-thione (IIIc) Yield 2.60 g (63%), mp 164–167°C IR spectrum, ν, cm–1: 3445, 3311, 3216 (NH), 1630 (CH=CH2), 1058 (C=S) 1H NMR spectrum, δ, ppm: 3.47 d.d (1H, NCH2, J 12.3, J 5.0 Hz), 3.95–4.07 m, 4.22 m (4H, 2H and 2H resp., OCH2CH2O), 4.65 t (1H, H25, J 12.0 Hz), 4.76 d.d (1H, HC=CHHtrans, J 14.1, J 1.2 Hz), 5.00 d.d (1H, CH=CHcisH, J 9.0, J 1.2 Hz), 5.24 d.d (1H, NCH2, J 12.3, J 5.0 Hz), 5.29 d.d (1H, H1, J 12.0, J 1.3 Hz), 5.44 d (1H, H21, J 12.0 Hz), 5.83 m (1H, CH=CH2), 6.80 br.s (1H, H 24), 6.81 d, 6.83 d (1H each, H6,16, J 7.8 Hz), 6.89 m (2H, H4,18), 7.18 m, 7.29 m (2H each, H3,19, H5,17) Mass spectrum, m/z (Irel, %): 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 JOURNAL OF ORGANIC CHEMISTRY Vol 47 No 2011 770 CHYONG KHONG KHIEU et al H 6.27; N 10.05 C22H25N3O3S Calculated, %: C 64.21; H 6.12; N 10.21 M 411.52 23-Imino-8,11,14-trioxa-22,24,25-triazatetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,16,18-hexaene (IIId) Yield 1.0 g (28%), mp 220–221°C IR spectrum, ν, cm–1: 3307, 3252 (NH), 3653, 1616 (C=N) 1H NMR spectrum, δ, ppm: 3.22 m (2H, H21,25), 3.73–4.15 m (6H, OCH2CH2O), 5.42 br.s (1H, H1), 6.81–7.46 m (10Harom, H22,24), 8.58 br.s (1H, C23=NH) Mass spectrum, m/z: 355 [M + 1]+ (ionization mode) Found, %: C 64.30; H 6.08; N 15.70 C19H22N4O3 Calculated, %: C 64.39; H 6.26; N 15.81 M 354.41 REFERENCES 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 Org Khim., 2008, vol 44, p 457; Le Tuan An’, Levov, A.N., Soldatenkov, A.T., and Gruzdev, R.D., Chyong Khong Khieu, Zh Org Khim., 2008, vol 44, p 463 Chyong Khong Khieu, Le Tuan An’, Levov, A.N., Nikitina, E.V., and Soldatenkov, A.T., Khim Geterotsikl Soedin., 2009, 1747 Sheldrick, G.M., Acta Cryst., 2008, A64, vol 112 RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol 47 No 2011 ... pyramidal configuration The sum of bond angles at these atoms equals 329.2° The triazine ring in the molecule IIIa has the conformation of a flattened boat (deviations of atoms C23 and N25 from the... IId, and 1.0 г (13 mmol) of ammonium acetate in a mixture of 30 ml of ethanol and ml of acetic acid was stirred for 13 h at 20°C The separated precipitate was filtered off, washed with ethanol, and. .. (rider model) and themal parameters [Uiso(H) = 1.2Uequiv(C)] All calculations were carried out using software SHELXTL [3] The tables of atomic coordinates, bond lengths and angles, and of the anisotropic