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 et
Trang 1Original 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
a Russian University of Peoples’ Friendship, Moscow, 117198 Russia
e-mail: soldatenkovat@yandex.ru
b Vietnam State University, Hanoi University of Sciences, Vietnam
c Nesmeyanov 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 fi rst 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
O
O O CHO OHC
HN N H N
R 2
R 1
H2N NHR 1
R2
NH4OAc
1 2 3 4 5 6 7
12
9
15 16 17 18
19 20 21 22 25 24
+
+
IIIа _ IIId
Activated methyl and methylene groups of dialkyl
ketones are involved into the condensation with the
for-myl groups of 1,ω-bis(2-forfor-mylphenoxy)-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
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 impos-sibility) of the preparation by this procedure the fi rst 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 1H NMR spectrum of this azacrown, highly symmetric with respect to similar protons, two pro-tons 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 fi eld 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 identifi ed by their multiplicity and chemical shifts Yet for the unambiguous proof of the
Trang 2Fig 1 Molecular structure of complex (IIIa)·CHCl3 The
non-hydrogen 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
stereochemi-cal 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
quadran-gle 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 C s (m) that however in the crystal is slightly
distorted due to the formation of two unsymmetrical
intra-molecular 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 do not lie in the same plane (mean-square deviation
0.112 Ǻ) Atoms N22 and N24 have the planar-trigonal
confi guration (the sum of bond angles is 357.0 and 357.1°
respectively) which slightly tends to pyramidal because
of the intermolecular hydrogen bonds (see below) The atom N25 assumes the pyramidal confi guration The sum of bond angles at these atoms equals 329.2° The
triazine ring in the molecule IIIa has the conformation
of a fl attened boat (deviations of atoms C 23 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
asym-metric centers (C1 and C21) and in the crystalit is present
as a racemate with the relative confi guration 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
com-plex through an intermolecular hydrogen bonds (see the table and Fig 1) N24–H24N⋯Cl3 and C24–H24A⋯S1
(N24–H24N⋯Cl3’ and C 24–H24B⋯S1 in the case of the alternative position of the disordered chloroform
mol-ecule) 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-compo-nent reaction with dialdehyde I and ammonia as readily
Parameters of hydrogen bonds in complex (IIIa)·CHCl3
Parameters D–H, Å H⋯A, Å D⋯A, Å D–HAngle ⋯A,
deg
N22–H22N⋯S1#1 0.92 2.45 3.348(2) 166
N24–H24N⋯Cl3 0.90 2.69 3.574(2) 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
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.
Trang 3as 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
in-dicating 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
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 H 21 (d, J 12.0 Hz)
ap-peared at 4.65, 5.29, and 5.44 ppm The protons of the N-allyl moiety give rise to fi ve signals of the
appropri-ate multiplicity: 3.47 (d.d, J 12.3 and 5.0 Hz), 4.76
(d.d, 3J trans14.1 and 2J 1.2 Hz), 5.00 (d.d, 3J cis 9.0 and
2J 1.2 Hz), 5.24 (d.d, J 12.3 and 5.0 Hz) and 5.83 (m) ppm.
Bringing guanidine IId into analogous condensation with podand I and ammonia resulted in the successful
iso-lation 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, confi rmed 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.
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 fi rst 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
spectro-photometer Specord 75IR Analysis of reaction mixtures was performed, the purity of the isolated compounds was checked, and mass spectra were obtained on instruments
Fig 2 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.
Fig 3 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.
Trang 4Finnigan 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 refl
ec-tions 23770, number of independent refl ecec-tions 5942,
number of refl ections with I > 2σ(I) 4755 Number of
refi ned 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
refl ections were measured on an automatic three-circle
diffractometer Bruker APEX-II CCD (MOKα-radiation,
graphite monochromator, φ- and ω-scanning) The
struc-ture of complex of compound IIIa with a chloroform
molecule was solved by the direct method and refi ned 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 refi nement in the isotropic approximation with
the fi xed position and thermal parameters [Uiso(H) =
1.2Ueq(N)] The location of the other hydrogen atoms was
calculated geometrically and refi ned in the isotropic
ap-proximation using fi xed 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 2 ml of acetic
acid was stirred for 13 h at 20°C The separated precipitate
was fi ltered off, washed with ethanol, and purifi ed by
recrystallization from chloroform to obtained the product
as colorless crystals
8 , 11 , 1 4 Tr i o x a 2 2 , 2 4 , 2 5 t r i a z a t e t r a c y c
-lo[19.3.1.0 2,7 0 15,20
]pentacosa-2,4,6,15(20),16,18-hexaene-23-thioH (IIIa) Yield 2.70 g (73%), mp 188–
190°C IR spectrum, ν, cm–1: 3397, 3322 and 3195 (NH),
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, H 4,18 , J 7.6 Hz),
6.94 d (2H, H6,16 , J 8.0 Hz), 7.25 d (2H, H 3,19, J 7.6 Hz) 7.31 t (2H, H5,17 , J 8.0 Hz), 7.94 d (2H, H 22,24, 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
ion-ization 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-triazatetra-cyclo[19.3.1.0 2,7 0 15,20 ]pentacosa-2,4,6,15(20),16,18-hexaene-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, H 1 ,
J 12.4, J 2.2 Hz), 5.41 d (1H, H 21 , 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-triazatetracy-clo[19.3.1.0 2,7 0 15,20 ]pentacosa-2,4,6,15(20),16,18-hexaene-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=CH cis H, 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, H 1 ,
J 12.0, J 1.3 Hz), 5.44 d (1H, H 21 , J 12.0 Hz), 5.83 m
(1H, CH=CH2), 6.80 br.s (1H, H24), 6.81 d, 6.83 d (1H each, H6,16 , J 7.8 Hz), 6.89 m (2H, H 4,18), 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;
Trang 5H 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-triazatetracy-clo[19.3.1.0 2,7 0 15,20 ]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
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.,
Stroki-na, 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.
2 Chyong Khong Khieu, Le Tuan An’, Levov, A.N.,
Ni-kitina, E.V., and Soldatenkov, A.T., Khim Geterotsikl
Soedin., 2009, 1747.
3 Sheldrick, G.M., Acta Cryst., 2008, A64, vol 112.