Transformations of dibenzo(γ-oxopiperidino)aza-14-crowns-4 upon acylation. Molecular structure of dibenzo-16-crown-3

Article abstract of DOI:10.1134/S1070428008040246

The result of acylation of dibenzoaza-14-crowns-4 containing a 4-oxopiperidine fragment with acetic anhydride depends on the substituent on the nitrogen atom. The NH-substrates initially undergo acylation at the piperidine nitrogen atom, followed by enolization and O-acylation. The acylation of N-methyl derivatives is accompanied by cleavage of the piperidine ring at the C-N bond with formation of acetylamino-substituted dibenzo-16-crowns-3. The structure of the latter was determined by X-ray analysis.

Full text of DOI:10.1134/S1070428008040246

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 4, pp. 612–616. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.N. Levov, Le Tuan An’, A.T. Soldatenkov, Chyong Khong Khieu, V.N. Khrustalev, 2008, published in Zhurnal Organicheskoi
Khimii, 2008, Vol. 44, No. 4, pp. 617–620.
Transformations of Dibenzo(γ-oxopiperidino)aza-14-crowns-4
upon Acylation. Molecular Structure of Dibenzo-16-crown-3
A. N. Levova, Le Tuan An’a, A. T. Soldatenkova, Chyong Khong Khieua, and V. N. Khrustalevb
a Russian University of Peoples’Friendship, ul. Ordzhonikidze 3, Moscow, 117198 Russia
e-mail: asoldatenkov@mail.ru
b Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, Moscow, Russia
Received January 21, 2007
Abstract—The result of acylation of dibenzoaza-14-crowns-4 containing a 4-oxopiperidine fragment with
acetic anhydride depends on the substituent on the nitrogen atom. The NH-substrates initially undergo acylation
at the piperidine nitrogen atom, followed by enolization and O-acylation. The acylation of N-methyl derivatives
is accompanied by cleavage of the piperidine ring at the C–N bond with formation of acetylamino-substituted
dibenzo-16-crowns-3. The structure of the latter was determined by X-ray analysis.
DOI: 10.1134/S1070428008040246
The range of chemical transformations of most
known crown and aza crown ethers is fairly narrow
and is generally limited to complex formation with
metal ions [1]. Incorporation of an oxopiperidine
fragment into the macrocyclic crown ether system [2]
provides a unique possibility for considerably extend-
ing the scope of chemical modifications, while a com-
bination of oxopiperidine and polyether moieties in
a single macromolecule makes it possible to study the
effect of the polyether bridge on the direction and
efficiency of chemical reactions involving the piperi-
dine ring, especially in reactions with ionic reagents.
Functionalization of such aza crown ethers should
extend their diversity and potential of their biological
activity.
transformations of dibenzoaza-14-crowns-4 Ia, Ib,
IVa, and IVb in the acylation with acetic anhydride.
When compound Ia having no substituent on the nitro-
gen atom was treated with an equimolar amount of
acetic anhydride for a short time, we obtained the cor-
responding N-acetyl derivative IIa. Prolonged heating
of macrocyclic ketones Ia and Ib in the presence of
a large excess of acetic anhydride was accompanied by
their enolization with subsequent O-acylation, which
is a fairly rare case for 4-oxopiperidine systems [3]
(Scheme 1).
As a result, we isolated from the reaction mixtures
N,O-diacylated aza crown ethers IIIa and IIIb in good
yields. The IR spectra of IIIa and IIIb contained
strong absorption bands due to stretching vibrations of
both ester (1739–1745 cm–1) and amide carbonyl
groups (1638–1651 cm–1). In the mass spectra of these
The present work was aimed at studying how sub-
stituent on the nitrogen atom affects the direction of
Scheme 1.
O
O
OCOMe
R
R
R
Me
Me
R
(MeCO)2O
N
H
N
N
or
COMe
O
COMe
O
O
O
O
O
O
O
O
Ia, Ib
IIa
IIIa, IIIb
R = Me (a), Ph (b).
612

TRANSFORMATIONS OF DIBENZO(γ-OXOPIPERIDINO)AZA-14-CROWNS-4
613
Scheme 2.
O
O
R
Me
Me
O
R
R
R
N
(MeCO)2O
N
Me
O
O
O
O
O
O
IVa, IVb
Va, Vb
R = Me (a), Ph (b).
compounds, medium-intensity peaks (Irel 38–39%) of
the molecular ions were present. Both aza crown ethers
IIIa and IIIb displayed in the 1H NMR spectra double
sets of signals from the NCOMe protons and some
other protons in the vicinity of the amide group owing
to distortion of symmetry of the tetrahydropyridine
fragment.
spectra of double singlets from the 14-H proton in
a weak field (δ 8.10–8.14 ppm).
The molecular structure of dibenzo-16-crown-3 Va,
its conformational parameters, and the size of the
internal cavity were determined by X-ray analysis of
a single crystal (see figure). The coordinates of atoms,
bond lengths, and bond angles in molecule Va were
deposited to the Cambridge Crystallographic Data
Center. According to the X-ray diffraction data, the
size of the internal cavity in molecule Va (which is
a 16-membered crownophane), estimated as the double
average distance between the O1, O2, O3, C1, and
C4 atoms and the centroid of the C1C4O1O2O3
pentagon, is 4.86 Å. The conformation of the
C7O1C12C13O2C14C15O3C16 polyether fragment may be
described as t-g(+)-t-t-g(–)-t (where t stands for trans,
±180°, and g stands for gauche, ±60°).
The acylation of N-methyl-substituted aza crowns
IVa and IVb followed a different path. Regardless of
the substituent on C22 and C24, the piperidine ring was
cleaved at the C–N bond, and the products were
dibenzo-16-crowns-3 Va and Vb having an exocyclic
acetylamino group, which were isolated in up to 62%
yield (Scheme 2). The structure of compounds Va and
Vb was confirmed by spectral data (for preliminary
communication on the synthesis of compound Va, see
1
[4]). The H NMR spectra of Va and Vb contained
double sets of signals from protons in the amide
moiety with an intensity ratio of 1:1.5 for compound
Va and 1:2 for Vb. The formation of a C13=C14HAr
Molecule Va possesses two asymmetric centers, C4
and C5; so that compound Va in crystal is a racemic
mixture of a diastereoisomer in which the relative con-
figuration of the above chiral centers is (4S*,5R*). The
1
fragment follows from the presence in the H NMR
O5
O4
C3
C26
C22
N11
C5
C25
C24
C2
C1
C4
C11
C18
C17
C6
C23
O1
O3
C19
C20
C14
C13
C10
C16
C7
C15
O2
C9
C12
C8
C21
Structure of the molecule of (10R*,11S*)-(13E)-10-[acetyl(methyl)amino]-11,13-dimethyl-8,9:15,16-dibenzo-1,4,7-trioxacyclo-
hexadeca-8,13,15-trien-12-one (Va) according to the X-ray diffraction data; non-hydrogen atoms are shown as thermal ellipsoids
with a probability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 4 2008

LEVOV et al.
614
Principal crystallographic data for (10R*,11S*)-(13E)-10-
[acetyl(methyl)amino]-11,13-dimethyl-8,9:15,16-dibenzo-
1,4,7-trioxacyclohexadeca-8,13,15-trien-12-one (Va) and
refinement parameters
muconatesemialdehyde decarboxylase, as well as to
inhibit seborrhea and treat myocardial ischemia with
probabilities of 77% and 66%, respectively.
EXPERIMENTAL
Parameter
Value
1
Formula
C28H35NO6
481.57
120
The H NMR spectra were recorded on a Bruker
Molecular weight
Temperature, K
Crystal system
Space group
a, Å
WP-400 spectrometer (400 MHz) using CDCl3 as sol-
vent. The mass spectra (electron impact, 70 eV) were
obtained on a Finnigan MAT Incos 50 mass spectrom-
eter with direct sample admission into the ion source.
The IR spectra were measured in KBr on a Specord
75IR instrument. Preparative column chromatography
was performed on aluminum oxide (100–160 μm). The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates. Aza
crowns Ia and IVa were synthesized according to the
procedures described in [2, 4].
Triclinic
P-1
09.4557(9)0
14.3143(13)
19.7965(18)
86.081
81.562
72.780
2530.8
4
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Å3
X-Ray diffraction study of compound (Va). The
unit cell parameters and reflection intensities were
determined on a Bruker SMART 1000 CCD automatic
diffractometer (MoKα irradiation, graphite mono-
chromator, θ- and ω-scanning). The principal crystallo-
graphic data and refinement parameters are given in
table. The structure was solved by the direct method
and was refined by the full-matrix least-squares proce-
dure in anisotropic approximation for non-hydrogen
atoms. Hydrogen atoms were localized objectively by
Fourier difference syntheses, and their positions were
refined in isotropic approximation. All calculations
were performed using SHELXTL PLUS software
package [6].
Z
d
calc, g/cm3
1.264
F(000)
μ, mm–1
1032
0.088
2θmax, deg
52
Total number of reflections
Number of independent reflections
21089
09864
04980
Number of independent reflections
with I > 2σ(I)
Number of refined parameters
R1 [from reflections with I > 2σ(I)]
wR2 (from all reflections)
Goodness of fit
00188
0.0675
0.1896
1.0050
22,24-Diphenyl-8,11,14-trioxa-25-azatetracyclo-
[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),16,18-hexaen-
23-one (Ib) and its 25-methyl derivative (IVb) were
synthesized as described in [2].
two senior substituents at the C1=C2 are oriented trans
with respect to each other. A unit cell of Va includes
two crystallographically independent molecules that
are enantiomeric. The only difference between them is
the degree of openness of the internal cavity, which is
determined by the dihedral angle between the planes
of the benzene rings (66.6° in one molecule and 46.4°
in the other).
Compound Ib. Yield 3.41 g (68%), mp 244–
246°C. IR spectrum, ν, cm–1: 3275 (NH), 1705 (C=O).
1H NMR spectrum, δ, ppm: 4.07–4.35 m (10H,
OCH2CH2O, 22-H, 24-H, NH), 4.68 t (1H, OCH2-
CH2O, J = 12.6 Hz), 4.79 d (2H, 1-H, 21-H, J =
10.8 Hz), 6.59 t (2H, 4-H, 18-H, J = 7.4 Hz), 6.72 d
(2H, 6-H, 16-H, J = 8.1 Hz), 6.77 d (2H, 3-H, 19-H,
J = 7.4 Hz), 7.01–7.15 m (12H, Harom). Mass spectrum,
m/z (Irel, %): 505 [M]+ (32), 477 (16), 387 (13), 386
(12), 297 (35), 296 (60), 208 (21), 178 (38), 165 (54),
152 (25), 131 (38), 118 (100), 91 (54), 90 (84), 89
(43). Found, %: C 78.23; H 6.25; N 2.59. C33H31NO4.
Calculated, %: C 78.39; H 6.18; N 2.77.
Using PASS Internet program [5], we made an at-
tempt to predict possible biological activity of the ob-
tained compounds. The results showed that aza crown
Ib and its N,O-diacetyl derivative IIIb may be interest-
ing as inhibitors of topoisomerase I (with a probability
of 75 and 69%, respectively), cardioprotectors (69 and
59%), and cell membrane permeability inhibitors (61
and 54%). Enol acetate IIIb was also predicted with
a high probability (87%) to inhibit aminocarboxy-
Compound IVb. Yield 1.04 g (20%), mp 234–
236°C. IR spectrum: ν 1698 cm–1 (C=O). H NMR
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 4 2008

TRANSFORMATIONS OF DIBENZO(γ-OXOPIPERIDINO)AZA-14-CROWNS-4
615
spectrum, δ, ppm: 1.71 s (3H, Me), 3.87 d (2H, 1-H,
21-H, J = 14.8 Hz), 3.93–4.13 m (8H, OCH2CH2O),
5.34 d (2H, 22-H, 24-H, J = 14.8 Hz), 6.54–7.14 m
(18H, Harom). Mass spectrum, m/z (Irel, %): 519 [M]+
(100), 491 (8), 401 (5), 400 (4), 178 (10), 165 (19),
135 (28), 119 (17), 118 (34), 91 (23), 90 (23). Found,
%: C 78.75; H 6.32; N 2.83. C34H33NO4. Calculated,
%: C 78.59; H 6.40; N 2.70.
group gave double signals belonging to the Z and E
isomers): 1.18 d and 1.22 d (1.2H and 1.8H, respec-
tively, 22-Me, J = 6.80 Hz), 1.49 s and 1.55 s (1.2H
and 1.8H, respectively, 24-Me), 2.29 s (3H, OCOMe),
2.46 s and 2.54 s (1.8H and 1.2H, respectively,
NCOMe), 3.12 q.q (1H, 22-H, J = 6.76, 0.8 Hz), 3.30–
4.46 m (9H, OCH2CH2O, 21-H), 5.13 d and 5.54 d
(0.6H and 0.4H, respectively, 1-H, J = 0.8 Hz), 6.09–
6.91 m (7H, Harom), 7.64 d and 7.87 d (0.4H and 0.6H,
respectively, Harom, J = 7.44 Hz). Mass spectrum, m/z
(Irel, %): 465 [M]+ (38), 422 (78), 406 (10), 380 (100),
364 (36), 176 (12), 91 (9). Found, %: C 69.35; H 6.83;
N 3.21. C27H31NO6. Calculated, %: C 69.66; H 6.71;
N 3.01.
25-Acetyl-22,24-dimethyl-8,11,14-trioxa-25-aza-
tetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),-
16,18-hexaen-23-one (IIa). A solution of 0.5 g
(1.3 mmol) of aza crown Ia and 1.4 g (1.3 mmol) of
acetic anhydride in 5 ml of pyridine was heated for 1 h
under reflux. The mixture was cooled and diluted with
water, and the precipitate was filtered off, dried, and
purified by recrystallization from ethanol. Yield 0.41 g
(76%), mp 170–172°C. IR spectrum, ν, cm–1: 1699
25-Acetyl-22,24-diphenyl-8,11,14-trioxa-25-aza-
tetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),-
16,18,23-heptaen-23-yl acetate (IIIb). Yield 0.49 g
(63%), mp 257–258°C. IR spectrum, ν, cm–1: 1745
1
(C=O, ketone), 1641 (C=O, amide). H NMR spec-
1
(C=O, ester), 1651 (C=O, amide). H NMR spectrum,
trum, δ, ppm: 1.37 d (3H, Me, J = 6.80 Hz), 1.44 d
(3H, Me, J = 6.86 Hz), 2.60 s (3H, COMe), 3.31 m and
3.42 m (1H each, 22-H, 24-H), 3.68–4.20 m (8H,
OCH2CH2O), 5.45 br.s and 6.32 br.s (1H each, 1-H,
21-H), 6.50 m (4H, 4-H, 6-H, 16-H, 18-H), 6.88 m
(4H, 3-H, 5-H, 17-H, 19-H). Mass spectrum, m/z
(Irel, %): 423 [M]+ (46), 395 (20), 380 (70), 364 (100),
352 (71), 220 (21), 207 (36), 203 (67), 176 (28), 162
(55), 133 (31), 91 (33). Found, %: C 70.81; H 7.15;
N 3.10 C25H29NO5. Calculated, %: C 70.90; H 6.90;
N 3.31.
δ, ppm: 1.53 s and 2.05 s (2H and 1H, respectively,
NCOMe), 1.96 s (3H, OCOMe), 3.44–4.26 m (10H,
OCH2CH2O, 21-H, 22-H), 4.74 s and 5.33 s (0.67H
and 0.33H, respectively, 1-H), 6.05–7.53 m (17H,
Harom), 8.54 d (1H, Harom, J = 7.40 Hz). Mass spectrum,
m/z (Irel, %): 589 [M]+ (39), 546 (65), 504 (100), 488
(16), 487 (5), 486 (6), 165 (5), 43 (47). Found, %:
C 75.13; H 6.05; N 2.25. C37H35NO6. Calculated, %:
C 75.36; H 5.98; N 2.38.
(10R*,11S*)-(13E)-10-[Acetyl(methyl)amino]-
11,13-dimethyl-8,9:15,16-dibenzo-1,4,7-trioxacyclo-
hexadeca-8,13,15-trien-12-one (Va). Yield 0.35 g
(62%), mp 160–162°C. IR spectrum, ν, cm–1: 1734
(C=O, ketone), 1640 and 1663 (C=O, amide). 1H NMR
spectrum, δ, ppm: 0.87 d and 0.90 d (1.8H and 1.2H,
Crown ethers IIIa, IIIb, Va, and Vb (general
procedure). A solution of 1.3 mmol of aza crown Ia,
Ib, IVa, or IVb in a mixture of 2.5 ml (25 mmol) of
acetic anhydride and 2 ml (25 mmol) of pyridine was
heated for 5–10 h under reflux. The solvent was
distilled off under reduced pressure, the residue was
treated with 20 ml of a saturated solution of sodium
carbonate and extracted with chloroform (3×20 ml),
the extracts were combined, dried over anhydrous
MgSO4, and evaporated under reduced pressure, and
the residue was subjected to column chromatography
on aluminum oxide using hexane–ethyl acetate (2:1)
as eluent. The product was additionally purified by
recrystallization from ethanol. Compounds IIIa, IIIb,
Va, and Vb were isolated as colorless crystalline
substances.
3
respectively, 11-Me, J = 16.6 Hz), 1.86 d and 1.99 d
4
(1.2H and 1.8H, respectively, 13-Me, J = 2.4 Hz),
2.02 s and 2.05 s (1.8H and 1.2H, respectively, COMe),
2.92 s and 2.95 s (1.8H and 1.2H, respectively, NMe),
3.78–4.23 m (8H, OCH2CH2O), 4.83–4.93 m (1H,
11-H), 5.07 d and 5.81 d (0.6H and 0.4H, respectively,
3
10-H, J = 11.0 Hz), 6.77–7.5 m (8H, Harom), 8.1 br.s
and 8.14 br.s (0.6H and 0.4H, respectively, 14-H).
Mass spectrum, m/z (Irel, %): 437 [M]+ (32), 394 (38),
365 (12), 364 (37), 338 (17), 135 (100), 132 (92), 119
(67). Found, %: C 71.21; H 7.28; N 3.41. C26H31NO5.
Calculated, %: C 71.37; H 7.14; N 3.20.
25-Acetyl-22,24-dimethyl-8,11,14-trioxa-25-aza-
tetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),-
16,18,23-heptaen-23-yl acetate (IIIa). Yield 0.64 g
(53%), mp 239–241°C. IR spectrum, ν, cm–1: 1739
10-[Acetyl(methyl)amino]-11,13-diphenyl-
8,9:15,16-dibenzo-1,4,7-trioxacyclohexadeca-8,13,15-
trien-12-one (Vb). Yield 0.53 g (73%), mp 122–
124°C. IR spectrum, ν, cm–1: 1720 (C=O, ketone),
1
(C=O, ester), 1638 (C=O, amide). H NMR spectrum,
1
δ, ppm (some protons in the vicinity of the amide
1638 and 1653 (C=O, amide). H NMR spectrum, δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 4 2008

LEVOV et al.
616
2. 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.,
Russ. J. Org. Chem., 2007, vol. 43, p. 456; Le Tuan An’,
Levov, A.N., Soldatenkov, A.T., Gruzdev, R.D., and
Chyong Khong Khieu, Russ. J. Org. Chem., 2007,
vol. 43, p. 462.
3. Mobio, I.G., Soldatenkov, A.T., Fedorov, V.O., Age-
ev, E.A., Turdebekov, K.M., Struchkov, Yu.T., Aki-
mov, V.M., and Prostakov, N.S., Khim. Geterotsikl.
Soedin., 1990, p. 1352; Soldatenkov, A.T., Levov, A.N.,
Mobio, I.G., Polyakova, E.I., Kutyakov, S.V., Le Tuan
An’, Komarova, A.I., Polyanskii, K.B., Andreeva, E.I.,
and Minaev, L.I., Khim.-Farm. Zh., 2003, vol. 37, p. 16.
ppm: 2.18 s and 2.36 s (1H and 2H, respectively,
NCOMe), 3.26 br.s (3H, NMe), 3.95–4.45 (8H, OCH2-
CH2O), 5.62 d and 6.34 d (0.33H and 0.66H, respec-
3
tively, 10-H, J = 11.8 Hz), 6.25 d (1H, 11-H, J =
11.8 Hz), 6.55–7.33 m (18H, Harom), 8.56 s and 8.64 s
(0.33H and 0.66H, respectively, 14-H). Mass spectrum,
m/z (Irel, %): 561 [M]+ (78), 533 (28), 518 (20), 488
(29), 444 (16), 235 (21), 194(92), 165 (20), 135 (71),
91 (36), 77 (14), 56 (61), 43 (100). Found, %: C 77.03;
H 6.07; N 2.51. C36H35NO5. Calculated, %: C 76.98;
H 6.28; N 2.49.
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5. Sadym, A.V., Lagunin, A.A., Filimonov, D.A., and Poroi-
kov, V.V., Khim.-Farm. Zh., 2002, vol. 36, p. 21.
6. Sheldrick, G.M., SHELXTL, V5.10, Madison: Bruker
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