New synthesis of tetraoxaspirododecane-diamines and tetraoxazaspirobicycloalkanes

Article abstract of DOI:10.1039/c9ra06372b

An efficient method for the synthesis of new spiro-tetraoxadodecanediamines and tetraoxazaspirobicycloalkanes has been developed by reactions of primary arylamines with gem-dihydroperoxides and α,ω-dialdehydes (glyoxal, pentanedial) catalyzed by lanthanid

Full text of DOI:10.1039/c9ra06372b

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New synthesis of tetraoxaspirododecane-diamines
and tetraoxazaspirobicycloalkanes†
Cite this: RSC Adv., 2019, 9, 29949
*
*
Kamil R. Shangaraev, Lilya U. Dzhemileva,
Nataliya N. Makhmudiyarova,
Tatyana V. Tyumkina, Ekaterina S. Mescheryakova, Vladimir A. D'yakonov,
Askhat G. Ibragimov and Usein M. Dzhemilev
An efficient method for the synthesis of new spiro-tetraoxadodecanediamines and
tetraoxazaspirobicycloalkanes has been developed by reactions of primary arylamines with gem-
dihydroperoxides and a,u-dialdehydes (glyoxal, pentanedial) catalyzed by lanthanide catalysts.
A
potential pathway for formation of tetraoxaspirododecane-diamines and tetraoxazospirobicycloalkanes
has been proposed that involves generation of intermediate tetraoxaspiroalkanediols under the reaction
conditions. The structures of the crystalline products have been confirmed by XRD. It was shown that
the synthesized tetraoxazaspirobicycloalkanes exhibit high cytotoxic activity against Jurkat, K562, and
U937 tumor cultures and Fibroblasts.
Received 15th August 2019
Accepted 16th September 2019
DOI: 10.1039/c9ra06372b
rsc.li/rsc-advances
Presence of a heteroatom at a-position relative to the
peroxide group in such compounds as artemisinin, artemether,
DU-1301, OZ277,3 veruculogen13 and fumitremorgin,14 and in
bicyclic15 and acyclic6 a-amino endoperoxides16 accounts for
antimalarial and antimicrobial activities of these compounds.
The data available on heteroatom-containing peroxides with
high antimalarial activity1,13 suggest that tetraoxaspir-
ocycloalkanediamines could be useful for the development of
antimalarial agents.
Introduction
Discovery of the antimalarial activity of the natural peroxide
compound artemisinin stimulated the development of
synthetic routes leading to novel cyclic peroxides.1 According to
the published data,2 tetraoxaspirocycloalkanes demonstrate, in
vivo, high antimalarial activity comparable with that of arte-
misinin.3 Known methods to synthesize tetraoxaspir-
ocycloalkanes include reactions of gem-dihydroperoxides with
a,u-dihaloalkanes in the presence of CsOH in DMF4 or the same
in the presence of Ag2O in CH2Cl2.2,5 Additionally, tetraox-
aspirocycloalkanes can be synthesized from unsaturated
hydroperoxides6 or (alkenyldioxy)cyclododecyl hydroperoxides.7
However, known synthetic methods to obtain tetraoxaspir-
ocycloalkanes are hindered by signicant drawbacks, such as
low yields of the target products2,4,5 and a multistage synthetic
process.2,6 One of the effective methods for the synthesis of
heteroatomic compounds of various structures in one stage
with a good yield are catalytic multicomponent reactions.7–12
Present communication concerns a new approach to the
synthesis of tetraoxaspirocycloalkanes having amine substitu-
ents at a-positions relative to peroxide groups and of tetraox-
azabicycloalkanes, via reactions of primary arylamines with
gem-dihydroperoxides and a,u-dialdehydes catalyzed by
lanthanide complexes.
Result and discusion
During preliminary experiments it has been shown that the
reaction of 1,1-dihydroperoxycyclohexane 1 with an equi-
molar amount of glyoxal 2 and p-chloroaniline 3a in selected
conditions (ꢀ20 ꢁC, THF, 6 h) catalyzed by 5 mol% of
Sm(NO3)3$6H2O gives N,N0-bis(4-chlorophenyl)-7,8,11,12-
tetraoxaspiro[5.6]dodecane-9,10-diamine 4a in 87% yield
(Scheme 1). The Sm(NO3)3$6H2O catalyst has been selected
due to its activity in the syntheses of pentaoxacanes,17 tet-
raoxazaspiroalkanes,18,19 and hexaoxazadispiroalkanes.20 In
an absence of the catalyst, the aforesaid reaction proceeds
with the formation, along with the target product 4a (10%),
of N-(4-chlorophenyl)formamide (70%) and cyclohexanone
(10%). Whether the reaction is conducted in presence of
other lanthanide catalysts, the yield of N,N0-bis(4-
chlorophenyl)-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-
diamine 4a decreases in the following order: La(NO3)3$6H2O
(80%) > TbCl3$6H2O (73%) > Ho(NO3)3$5H2O (60%) >
DyCl3$6H2O (51%) > NdCl3 $6H2O (50%).
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt
Oktyabrya, 450075 Ufa, Russian Federation. E-mail: natali-mnn@mail.ru;
dzhemilev@mail.ru
† Electronic supplementary information (ESI) available. CCDC 1905323, 1905327,
1905330, 1905341, 1905334, 1905337. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c9ra06372b
In selected conditions [5 mol% Sm(NO3)3$6H2O, 20 ꢁC, 6 h],
arylamines (m,p-uoroanilines, p-bromoaniline) 3b–e enter the
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Scheme 1 Synthesis of tetraoxaspirododecane-diamines.
been stipulated by the fact that both the reactants and the target
products are highly soluble in THF.
Structures
of
N,N0-bis(aryl)-7,8,11,12-tetraoxaspiro[5.6]
1
dodecane-9,10-diamines 4a–e have been established using H
and 13C NMR spectrometry methods, MALDI TOF/TOF mass
spectrometry and X-ray diffraction (Fig. 1). In 1H NMR spectra,
the signals for methine hydrogens atoms localized between
the N and O atoms in the seven-membered rings resonate in
a region between 4.60–4.75 ppm and emerge as a broadened
singlet due to slow, in the NMR time scale, conformational
exibility of the ring, whereas methylene protons of the spi-
roalkane and alkane moieties occur as two multiplets in the
regions between 1.40–1.70 ppm and 2.40–2.70 ppm. Aromatic
protons resonate in a low-eld region between 6.80–7.40 ppm.
The mass spectrum of the heterocycles 4a–e displays the cor-
responding molecular ion peaks, accordingly.
Crystals for the compounds 4a, b, d, e (Fig. 1) have been
obtained from a solvent mixture of hexane and Et2O in 10 : 1
ratio, at room temperature. In the corresponding structures,
a spiro-conjugated tetraoxepane ring adopts a twist boat
conformation, similarly to the tetraoxepane derivative
described in the literature.6 Chiral centers at atoms C9 and C10
adopt S conguration in the compounds 4a, 4d, and 4e and R
conguration in the compound 4b. N-aryl substituents are anti-
oriented relative to each other, whereupon the torsion angle
N20–C10–C9–N13 constitutes 73.1(3), ꢂ79.4(2), 68.7(4) and
74.3(8) for the compounds 4a, 4b, 4d, and 4e, respectively. The
cyclohexane moiety in all compounds 4a, b, d, e adopts a chair
conformation. In all molecules, the nitrogen atoms adopt
a planar conguration (wherein the sum of angles at the
Fig. 1 Molecular structure of peroxides 4a, b, d, e. The atoms are
depicted as thermal ellipsoids (p ¼ 50%).
reaction with glyoxal 2 and 1,1-dihydroperoxycyclohexane 1 to
result in formation of corresponding N,N0-bis(aryl)-7,8,11,12-
tetraoxaspiro[5.6]dodecane-9,10-diamines 4b–d in 84–90%
yields (Scheme 1). In the experiments, choice of the solvent has
Scheme 2 Synthesis of tetraoxazaspirobicycloalkanes.
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Scheme 3 Synthesis of tetraoxaspirocycloalkanediols.
Fig. 2 Molecular structure of peroxide 12b. The atoms are depicted as
thermal ellipsoids (p ¼ 50%).
the compound 12b adopts a planar conformation similarly to
that occurring in the compounds 4a, b, d, e (with the sum of
P
angles at the nitrogen, N006 ¼ 359.7ꢁ).
nitrogen atom is ꢀ360ꢁ), due to conjugation between the p-
system of the aromatic substituent and an unshared pair of
electrons at the nitrogen atom. The lengths of peroxide bonds
As can be viewed from the gure, in a crystal phase the
diperoxide moiety in the bicyclic structure adopts the chair
conformation, while in solution a multicomponent conforma-
tional equilibrium exists, which is typical of both triperoxide20
and azadiperoxide18,19 compounds. Thus, in the 13C NMR
spectra of the synthesized compounds 11–16, three signals with
similar chemical shis can be observed in a region between
85.92–86.87 ppm for each said compound, instead of individual
signals characteristic of the bridgehead tertiary carbon atoms.
At the same time, the methine protons also exhibit signals split
into components with different intensity in the matching region
5.36–5.83 ppm of the 1H NMR spectra. By the way of an example,
for the compound 12a, the integrated intensity ratio for signals
at 5.83 ppm, 5.68 ppm, and 5.37 ppm constitutes 1 : 8 : 1, which
correlates with the carbon signals at 85.92 ppm, 86.87 ppm, and
86.75 ppm, respectively, according to the data obtained by
heteronuclear 2D HSQC spectroscopy. In order to assign signals
in the NMR spectra and by using quantum chemical method
B3LYP/6-31G(d,p), six stable conformers have been identied
on a potential energy surface of the bicyclic tetraoxazaspir-
oalkane molecule 12a having the spirohexane substituent in the
chair conformation.22 Three the most energetically favorable
conformers are shown in Fig. 3 as preferred candidates for the
structures observed in the NMR spectra.
ꢀ
are provided within a range of 1.458 to 1.468 A.
In order to expand the scope of applicability of the method
developed hereby, we have conducted a reaction of pentane-1,5-
dial 5 with gem-bis-hydroperoxides and primary amines. In
conditions determined for the cyclocondensation of glyoxal 2
(5 mol% Sm(NO3)3$6H2O, 20 ꢁC, 6 h), the pentane-1,5-dial 5
enters the reaction with gem-bis-hydroperoxides and primary
amines to give tetraoxazaspirobicycloalkanes (Scheme 3). In the
reaction, the 1,1-dihydroperoxycycloalkane compounds based
on cyclohexane 1, cyclopentane 6, 4-methylcyclohexane 7,
cyclooctane 8, dodecane 9 and adamantane 10 have been
utilized as gem-bis-hydroperoxides, whereas arylamines 3a–g
have been utilized as the primary amines. The results obtain-
able in selected cyclocondensation conditions [pentane-1,5-
dial : gem-bis-hydroperoxide : arylamine : Sm(NO3)3$6H2O
¼
ꢁ
1 : 1 : 1 : 0.05 (mol/mol); THF; 20 C] indicate that the method
thus developed is an efficient tool for the selective synthesis of
bicyclic tetraoxazaspirobicycloalkanes 11–16 (71–83%) (Scheme
2). N-arylpiperidines 17a–g21 were isolated as by-products of the
reaction with a yield not exceeding 25%.
Crystals for the compound 12b (Fig. 2) have been obtained
from a solvent mixture of hexane and Et2O in 10 : 1 ratio, at
room temperature.
According to the X-ray diffraction data, a tetraoxazocane ring
adopts a boat chair conformation, whereas cyclohexane and
pyran rings adopt the chair conformation. Bond lengths of the
peroxide bonds O001–O003 and O002–O004 constitute 1.4692
According to the calculated data, the global minimum
corresponds to a conformer A that occurs in the crystal phase.
Slightly higher in energy conformational states of the spi-
roaminodiperoxide moiety are the twist chair (B) and the chair
(C). For the conformation B, a conformation B0 of similar energy
may exist, due to a lack of symmetry upon rigid xation of
rotational position of the N-substituent and the spiro moiety.
Symmetry violation is also possible in an event of ortho- or meta-
ꢀ
(14) and 1.4612 (14) A, respectively. The nitrogen atom N006 in
Fig. 3 Optimized structures of the lowest energy conformers of Fig. 4 Structure of compound 19 according to X-ray diffraction. The
tetraoxazaspirobicycloalkanes.
atoms are depicted as thermal ellipsoids (p ¼ 50%).
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Table 1 Cytotoxic activities in vitro of compounds 4a, b, 11a, e, 12b, c, 15a measured on tumor cell cultures (Jurkat, K562, U937, Fibroblasts) (mM)
C-d
Jurkat (IC50, mM)
K562 (IC50, mM)
U937 (IC50, mM)
Fibroblasts (IC50, mM)
11e
11a
12c
14g
12b
15a
4b
13.51 ꢃ 0.72
63.29 ꢃ 2.25
17.39 ꢃ 1.87
272.57 ꢃ 5.68
15.48 ꢃ 0.31
118.23 ꢃ 2.74
52.91 ꢃ 1.41
>500
12.38 ꢃ 0.67
45.13 ꢃ 1.36
12.35 ꢃ 1.18
45.87 ꢃ 1.73
15.09 ꢃ 0.18
61.34 ꢃ 2.08
28.37 ꢃ 1.34
106.24 ꢃ 3.95
16.44 ꢃ 1.43
42.19 ꢃ 1.24
11.49 ꢃ 0.84
40.87 ꢃ 1.58
14.83 ꢃ 0.24
59.17 ꢃ 1.79
26.45 ꢃ 1.17
141.28 ꢃ 4.33
127.63 ꢃ 2.59
231.42 ꢃ 3.88
145.19 ꢃ 3.47
368.68 ꢃ 4.53
129.42 ꢃ 2.37
389.23 ꢃ 4.69
249.37 ꢃ 3.91
>500
4a
substitutions in the aromatic ring, which can cause doubling of
the observed set of signals. Additionally, any changes in the
bicyclic cage lead to a sharp increase in energy up to
28 kcal molꢂ1 and higher (ESI,† conformers D and E); therefore,
these changes are unlikely.
Presumably, the scheme of formation of spiro-tetraoxepanes
includes the initial formation of tetraoxaspirocycloalkanediols,
which then undergo condensation with primary amines to give
the target products. This assumption was veried by conducting
the synthesis of tetraoxaspirocycloalkanediols 18–20 by the
reaction of 1,1-dihydroperoxycycloalkanes 1, 6, and 7 with
glyoxal 2 in the presence of 5 mol% of the Sm(NO3)3$6H2O
catalyst (Scheme 3). Without a catalyst, the yield of diols 17–19
did not exceed 10%.
Conclusions
Hence, a versatile method has been developed for the synthesis
of new spiro-tetraoxepanediamines and tetraoxazaspir-
obicycloalkanes by the reactions of primary arylamines with
gem-dihydroperoxides and a,u-dialdehydes in presence of
lanthanide catalysts. The method thus developed markedly
expands structural diversity of nitrogen-containing cyclic
diperoxide derivatives and, in most cases, allows synthesizing
these compounds with higher yields (up to 95%) and selectivity.
In addition, it was shown that the synthesized spiro-
tetraoxepanediamines
exhibit high cytotoxic activity against Jurkat, K562, U937 tumor
cultures and Fibroblasts.
and
tetraoxazaspirobicycloalkanes
According to X-ray diffraction data for compounds 19 (Fig. 4),
in the crystalline state, the tetraoxepane and cyclohexane
moieties exist in the chair conformation. Like in structure 4b,
the chiral centers at the C005 and C008 carbon atoms have the R
conguration.
Cytotoxicity of azaperoxide based compounds is well
known,3,13,14,19,20b,23 so screened the representative compounds
for their cytotoxicity activity against Jurkat, K562, U937 Fibro-
blasts cell lines and results are summarized in Table 1.
Experimental section
General remarks
All reactions were performed at room temperature in air in
round-bottom asks equipped with a magnetic stir bar. The
NMR spectra were recorded on a Bruker Avance 500 spectrom-
eter at 500.17 MHz for 1H and 125.78 MHz for 13C according to
standard Bruker procedures. CDCl3 was used as the solvent,
and tetramethylsilane, as the internal standard. The mixing
time for the NOESY experiments was 0.3 s. Mass spectra were
recorded on a Bruker Autoex III MALDI TOF/TOF instrument
with a-cyano-4-hydroxycinnamic acid as a matrix. Samples were
prepared by the dried droplet method. The C, H, and N were
quantied by a Carlo Erba 1108 analyzer. The oxygen content
was determined on a Carlo Erba 1108 analyzer. The progress of
reactions was monitored by TLC on Sorbl (PTSKh-AF-A) plates,
with a 5 : 1 hexane : EtOAc mixture as the eluent and visuali-
zation with I2 vapor. For column chromatography, silica gel
MACHEREY-NAGEL (0.063–0.2 mm) was used.
All calculations were carried out using a program Gaussian
09. Geometric parameter optimization, vibrational frequency
analysis, and calculation of entropy and thermodynamic
corrections to the total energy of the compounds were carried
out on the B3LYP functional18 using the 6-31G(d,p) basis set. No
limitation was imposed on the changes in the geometric
parameters of the subsystems studied. Thermodynamic
parameters were determined at 298 K. The minima were
conrmed through the calculation of the force constant
(Hessian) matrix and the analysis of the resulting frequencies.
It
was
found
that
the
synthesized
spiro-
tetraoxadodecanediamines
4a,
f
and tetraoxazaspir-
obicycloalkanes 11a, e, 12b, c, 14g, 15a exhibit a cytotoxic effect
on all selected tumor cell lines in a wide range from 11.49 to
>500 mM. The most potent cytotoxic activity was shown by
peroxides 11e, 12c and 12b synthesized by the reaction of 1,1-
dihydroperoxycyclopentane 6 or 1,1-dihydroperoxycyclohexane
1
and uorine(bromine)arylamines. The replacement of
bromine or uorine atoms with chlorine atom in the phenyl
substituent of the studied peroxides 11a, 14g and 15a leads to
a signicant decrease in their cytotoxicity, with a pronounced
selective effect on myelocytic (K562) and monocytic (U937) cell
cultures, in comparison with the cytotoxicity of the studied
compounds to lymphocytes of the Jurkat line. At the same time,
spiro-tetraoxadodecanediamines with two uoroaromatic
substituents 4b or chloroaromatic 4a fragments showed less
cytotoxicity compared to tetraoxazaspirobicycloalkanes 11a, e,
12b, c, 14g, 15a.
The synthesized compounds have a selectivity index (SI) with
respect to all tumor cells from 4 to 10 (SI ¼ IC50 Fibroblasts/IC50
cancer cells).
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All minima were veried to have no negative frequencies. dialdehydes (glyoxal, pentanedial) (10 mmol), and specied
Visualization of quantum chemical data was carried out with gem-dihydroperoxides (10 mmol).29 Then Sm(NO3)2$6H2O
the programs ChemCra.24
(0.062
g,
5
mol%
relative
to
1,10-peroxybis(1-
The X-ray diffraction measurements for compounds 4a, 4b, hydroperoxycycloalkane)) was added. The reaction mixture
4d, 4e, 12b, 19 were performed on an XCalibur Gemini Eos was stirred at ꢀ20 ꢁC for 1 h, aer which primary arylamines (20
automated four-circle diffractometer (graphite mono- mmol) was added, and the reaction mixture was stirred at
chromator, MoKa radiation, l ¼ 0.71073 A, u-scan mode, 2qmax ꢀ20 ꢁC for 6 h more. Aer completion of the reaction H2O (5 ml)
˚
¼ 62ꢁ) at ambient temperature (293–298 K). Collected data were and CH2Cl2 (5 ml) were added. The organic layer was separated,
processed using the program CrysAlisPro.25 Structures deter- dried (anhydrous MgSO4) and concentrated to isolate products
minations were carried out with the OLEX2 program.26 The stable during storage at room temperature. Products of the
structures were solved by direct methods and rened by the full- reaction were puried by column chromatography on SiO2
matrix least-squares method in the anisotropic approximation using 10 : 1 PE : Et2O as the eluent. The progress of reactions
for non-hydrogen atoms. All hydrogen atoms are generated was monitored by TLC, with a 5 : 1 hexane : EtOAc mixture as
using the proper HFIX command and rened isotropically using the eluent, visualization was performed with I2 vapor.
the riding model. The calculations were performed using the
SHELX program package.27 The molecular plots were drawn
using mercury.28
The synthesis of the gem-dihydroperoxides 1, 6–10 was as
reported in the literature.29 THF was freshly distilled over
N9,N10-bis(4-Chlorophenyl)-7,8,11,12-tetraoxaspiro[5.6]
dodecane-9,10-diamine 4a
White crystals; 0.37 g (87% yield), Rf 0.77 (PE/Et2O ¼ 10/1), mp
LiAlH4. Glyoxal was used as aqueous solution (40%).
120–122 ꢁC. 1H NMR (400 MHz, CDCl3, 25 ꢁC): d ¼ 1.28–1.48 (m,
2H, CH2), 1.69 (br.s, 4H, 2CH2), 1.77–1.89 (m, 4H, 2CH2), 5.57
Cell culturing
(br.s, 2H, 2CH), 7.13–7.15 (m, 4H, CH), 7.18–7.21 (m, 4H, CH).
Human cancer cell line HeLa was obtained from the HPA 13C NMR (100 MHz, CDCl3, 25 ꢁC): d ¼ 22.6 (conformer A), 22.8
Culture Collections (UK). Cells (Jurkat, K562, U937, Fibroblasts)
(conformers B+C), 25.1, 31.2 (conformer A), 31.4 (conformers
were purchased from Russian Cell Culture Collection (Institute
of Cytology of the Russian Academy of Sciences) and cultured
according to standard protocols and sterile technique. The cell
lines were shown to be free of viral contamination and myco-
plasma. Cells were maintained in RPMI 1640 (Jurkat, K562,
U937, Fibroblast) (Gibco) supplemented with 4 mM glutamine,
B+C), 85.1, 115.8, 116.3, 124.7, 128.6, 145.1. MALDI TOF/TOF,
m/z: 424 [M ꢂ H]+. Anal. calcd for C20H22Cl2N2O4: C, 56.48; H,
5.21; N, 6.59%. Found: C, 56.46; H, 5.19; N, 6.57%.
N9,N10-bis(2-Fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]
dodecane-9,10-diamine 4b
10% FBS (Sigma) and 100 units per ml penicillin–streptomycin
(Sigma). All types of cells were grown in an atmosphere of 5%
ꢁ
CO2 at 37 C. The cells were subcultured at 2–3 days intervals. White crystals; 0.33 g (85% yield), Rf 0.75 (PE/Et2O ¼ 10/1), mp
Cells were then seeded in 24 well plates at 5 ꢄ 104 cells per well 134–136 ꢁC. 1H NMR (400 MHz, CDCl3, 25 ꢁC): d ¼ 1.28–1.36 (m,
and incubated overnight. Jurkat, K562, U937, Fibroblast cells 2H, CH2), 1.43–1.45 (m, 4H, 2CH2), 1.60–1.61 (m, 4H, 2CH2),
were subcultured at 2 day intervals with a seeding density of 1 ꢄ 5.70 (br.s, 2H, 2CH), 6.87–6.89 (m, 2H, CH), 7.02–7.10 (m, 4H,
105 cells per 24 well plates in RPMI with 10% FBS.
CH), 7.18–7.24 (m, 2H, CH). 13C NMR (100 MHz, CDCl3, 25 ꢁC):
d ¼ 22.6, 25.1, 29.7, 89.7, 111.5, 114.5, 115.2 (J ¼ 19), 120.3 (J ¼
17), 124.7, 142.5, 164.1 (J ¼ 192). MALDI TOF/TOF, m/z: 391 [M
ꢂ H]+. Anal. calcd for C20H22F2N2O4: C, 61.22; H, 5.65; N, 7.14%.
Found: C, 61.20; H, 5.63; N, 7.11%.
Cytotoxicity assay
Viability (live/dead) assessment was performed by staining cells
with 7-AAD (7-aminoactinomycin D) (Biolegend). Aer treat-
ment cells were harvested, washed 1–2 times with phosphate-
buffered saline (PBS) and centrifuged at 400g for 5 min. Cell
pellets were resuspended in 200 mL of ow cytometry staining N9,N10-bis(3-Fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]
buffer (PBS without Ca2+ and Mg2+, 2.5% FBS) and stained with dodecane-9,10-diamine 4c
5 mL of 7-AAD staining solution for 15 min at room temperature
in the dark. Samples were acquired on NovoCyte TM 2000 Flow
Cytometry System (ACEA) equipped with 488 nm argon laser.
Detection of 7-AAD emission was collected through a 675/30 nm
White crystals; 0.34 g (85% yield), Rf 0.78 (PE/Et2O ¼ 10/1), mp
138–140 ꢁC. 1H NMR (400 MHz, CDCl3, 25 ꢁC): d ¼ 1.30–1.46 (m,
2H, CH2), 1.61 (br.s, 4H, 2CH2), 1.77–1.84 (m, 4H, 2CH2), 5.62
(br.s, 2H, 2CH), 6.58–6.68 (m, 6H, CH), 7.18–7.25 (m, 2H, CH).
lter in the FL4 channel.
13C NMR (100 MHz, CDCl3, 25 ꢁC): d ¼ 22.6 (conformer A), 22.7
(conformers B+C), 25.0 (conformer A), 25.2 (conformers B+C),
Cyclocondensation reactions of primary arylamines with gem-
31.2 (conformer A), 31.6 (conformers B+C), 88.2, 102.5 (J ¼
dihydroperoxides and a,u-dialdehydes (glyoxal, pentanedial)
7),111.1, 112.1, 107.2 (J ¼ 17), 130.7 (J ¼ 8), 145.6, 163.8 (J ¼
catalyzed by Sm(NO3)3$6H2O
195). MALDI TOF/TOF, m/z: 391 [M ꢂ H]+. Anal. calcd for
General procedure: a Schlenk vessel mounted on a magnetic
stirrer was charged at ꢀ20 ꢁC with tetrahydrofuran (5 ml), a,u- 5.63; N, 7.12%.
C20H22F2N2O4: C, 61.22; H, 5.65; N, 7.14%. Found: C, 61.19; H,
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2H, CH). 13C NMR (125.78 MHz, CDCl3, 25 ꢁC): d ¼ 14.3
(conformer A), 16.0 (conformers B+C), 23.3 (conformer A), 24.6
(conformers B+C), 24.9 (conformer A), 26.4 (conformer A), 27.1
(conformers B+C), 32.4 (conformers B+C), 33.5 (conformer A),
33.7 (conformers B+C), 34.6 (conformer A), 86.5 (conformer B),
87.1 (conformer A), 87.4 (conformer C), 113.1, 119.7
(conformers B+C), 120.50 (conformer A), 124.5, 131.6
(conformer A), 132.4 (conformer B+C), 149.2. MALDI TOF/TOF,
m/z: 369 [M ꢂ H]+. Anal. calcd for C16H20BrNO4: C, 51.91; H,
5.45; N, 3.78%. Found: C, 51.89; H, 5.43; N, 3.76%.
N9,N10-bis(4-Fluorophenyl)-7,8,11,12-tetraoxaspiro[5.6]
dodecane-9,10-diamine 4d
White crystals; 0.35 g (88% yield), Rf 0.74 (PE/Et2O ¼ 10/1), mp
128–130 ꢁC. 1H NMR (400 MHz, CDCl3, 25 ꢁC): d ¼ 1.28–1.45 (m,
2H, CH2), 1.61 (br.s, 4H, 2CH2), 1.77–1.89 (m, 4H, 2CH2), 5.57
(br.s, 2H, 2CH), 6.80–6.88 (m, 4H, CH), 6.96–7.01 (m, 4H, CH).
13C NMR (100 MHz, CDCl3, 25 ꢁC): d ¼ 22.6, 25.1, 31.2
(conformer A), 31.4 (conformers B+C), 89.4, 111.9, 116.0 (J ¼ 18),
121.6, 139.9, 157.7 (J ¼ 190). MALDI TOF/TOF, m/z: 391 [M ꢂ
H]+. Anal. calcd for C20H22F2N2O4: C, 61.22; H, 5.65; N, 7.14%.
Found: C, 61.20; H, 5.62; N, 7.12%.
11-(4-Chlorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclohexane] 12a
N9,N10-bis(4-Bromophenyl)-7,8,11,12-tetraoxaspiro[5.6]
Orange oil; 0.27 g (80% yield), Rf 0.75 (PE/Et2O ¼ 10/1). 1H NMR
(500.17 MHz, CDCl3, 25 ꢁC): d ¼ 1.57–1.62 (m, 1H, CHa,
conformers B+C), 2.11–2.20 (m, 1H, CHb, conformers B+C),
2.39–2.46 (m, 2H, CH2, conformer A), 1.44–1.62 (m, 4H, 2CH2),
1.44–1.50 (m, 4H, 2CH2), 1.78–1.87 and 1.97–2.00 (m, 4H,
2CH2), 1.31–1.34 and 2.20–2.24 (m, 4H, 2CH2), 5.37–5.38 (m,
2H, 2CH, conformer B), 5.68 (s, 2H, 2CH, conformer A), 5.84 (s,
2H, 2CH, conformer C), 7.05–7.19 (m, 1H, CH), 7.21–7.22 (m,
1H, CH), 6.89–6.95 (m, 1H, CH), 7.17–7.19 (m, 1H, CH). 13C
dodecane-9,10-diamine 4e
White crystals; 0.43 g (90% yield), Rf 0.72 (PE/Et2O ¼ 10/1), mp
122–124 ꢁC. 1H NMR (400 MHz, CDCl3, 25 ꢁC): d ¼ 1.28–1.48 (m,
2H, CH2), 1.63 (br.s, 4H, 2CH2), 1.77–1.85 (m, 4H, 2CH2), 5.56
(br.s, 2H, 2CH), 6.73–6.75 (m, 4H, CH), 7.34–7.35 (m, 4H, CH).
13C NMR (100 MHz, CDCl3, 25 ꢁC): d ¼ 22.6, 24.9, 30.7
(conformer A), 31.3 (conformers B+C), 89.3, 106.4, 112.2, 116.0,
121.5, 132.2. MALDI TOF/TOF, m/z: 513 [M ꢂ H]+. Anal. calcd for
C
20H22Br2N2O4: C, 46.72; H, 4.31; N, 5.45%. Found: C, 46.70; H,
ꢁ
NMR (125.78 MHz, CDCl3, 25 C): d ¼ 14.6 (conformer A), 16.2
4.29; N, 5.43%.
(conformers B+C), 22.0 (conformer A), 22.5 (conformers B+C),
22.7 (conformer A), 22.9 (conformer A), 25.3 (conformers B+C),
25.4 (conformers B+C), 26.4 (conformer A), 26.9 (conformers
B+C), 28.7 (conformer A), 29.7 (conformers B+C), 30.7
(conformer B+C), 31.2 (conformer A), 85.9 (conformer B), 86.8
(conformer C), 86.9 (conformer A), 108.8 (conformers B+C),
109.5 (conformers A), 116.2 (conformers B+C), 116.8 (conformer
A), 118.4 (conformers B+C), 119.0 (conformers A), 120.6
(conformers A), 121.3 (conformers B+C), 129.7 (conformers A),
129.9 (conformers B+C), 134.4, 151.2. MALDI TOF/TOF, m/z: 338
[M ꢂ H]+. Anal. calcd for C17H22ClNO4: C, 60.09; H, 6.53 N,
4.12%. Found: C, 60.07; H, 6.51 N, 4.10%.
11-(4-Chlorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclopentane] 11a
Brown oil; 0.24 g (75% yield), Rf 0.79 (PE/Et2O ¼ 10/1). 1H NMR
(500.17 MHz, CDCl3, 25 ꢁC): d ¼ 1.54–1.59 (m, 1H, CHa,
conformers B+C), 2.40–2.44 (m, 1H, CHb, conformers B+C),
2.13–2.19 (m, 2H, CH2, conformer A), 1.53–2.10 (m, 4H, 2CH2),
1.70–1.97 (m, 4H, 2CH2), 2.45–2.35 and 2.13–2.20 and 1.76–1.82
and 1.50–1.60 (m, 4H, 2CH2), 5.35–5.36 (m, 2H, 2CH, conformer
B), 5.65 (s, 2H, 2CH, conformer A), 5.77 (s, 2H, 2CH, conformer
C), 6.77–6.87 (m, 2H, CH), 7.13–7.20 (m, 2H, CH). 13C NMR
(125.78 MHz, CDCl3, 25 ꢁC): d ¼ 14.2 (conformer A), 16.0
(conformers B+C), 23.2 (conformer A), 24.3 (conformers B+C),
24.6 (conformer A), 26.4 (conformer A), 27.1 (conformers B+C),
33.5 (conformers B+C), 33.7 (conformer A), 34.0 (conformers
B+C), 34.2 (conformer A), 88.2 (conformer B), 88.9 (conformer
A), 89.1 (conformer C), 113.4, 114.2 (conformers B+C), 120.7
(conformer A), 128.0, 129.2 (conformer A), 140.2 (conformer
B+C), 159.7. MALDI TOF/TOF, m/z: 324 [M ꢂ H]+. Anal. calcd for
11-(2-Fluorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclohexane] 12b
Brown crystals; 0.26 g (83% yield), Rf 0.77 (PE/Et2O ¼ 10/1), mp
1
ꢁ
ꢁ
80–82 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 1.56–1.60
(m, 1H, CHa), 2.14–2.24 (m, 1H, CHb), 1.60–1.66 (m, 2H, CH2),
1.54–1.59 (m, 2H, CH2), 1.46–1.50 (m, 4H, 2CH2), 1.87–2.02 (m,
4H, 2CH2), 2.28–2.30 (m, 2H, CH2), 5.15 (d, 2H, J ¼ 10 Hz, 2CH,
conformer B), 5.34 (br.s, 2H, 2CH, conformer A), 5.44–5.45 (m,
2H, 2CH, conformer C), 6.93–7.12 (m, 3H, CH), 7.84–7.87 (m,
1H, CH). 13C NMR (125.78 MHz, CDCl3, 25 ꢁC): d ¼ 14.9
(conformer A), 16.4 (conformers B+C), 22.0 (conformer A), 22.6
(conformers B+C), 22.9 (conformer B+C), 22.9 (conformer A),
C
16H20ClNO4: C, 58.99; H, 6.19; N, 4.30%. Found: C, 58.97; H,
6.17; N, 4.27%.
11-(4-bromophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclopentane] 11e
Brown solid; 0.26 g (71% yield), Rf 0.77 (PE/Et2O ¼ 10/1), mp 25.4 (conformers B+C), 25.5 (conformers B+C), 26.1 (conformer
110–112 ꢁC. 1H NMR (500.17 MHz, CDCl3, 25 ꢁC): d ¼ 1.57–1.60 A), 30.8 (conformers B+C), 31.6 (conformer A), 88.9 (conformer
(m, 1H, CHa, conformers B+C), 2.43–2.47 (m, 1H, CHb, B), 89.3 (conformer A), 89.5 (conformer C), 108.7 (conformers
conformers B+C), 2.13–2.20 (m, 2H, CH2, conformer A), 1.57– B+C), 115.9 (J ¼ 17, conformers B+C), 116.1 (J ¼ 17 Hz,
2.11 (m, 4H, 2CH2), 1.70–1.97 (m, 4H, 2CH2), 2.47–2.39 and conformers A), 123.6 (J ¼ 6), 124.4, 124.8, 137.9 (J ¼ 6), 156.3 (J ¼
2.13–2.20 and 1.74–1.80 and 1.52–1.60 (m, 4H, 2CH2), 5.27–5.28 193). MALDI TOF/TOF, m/z: 322 [M ꢂ H]+. Anal. calcd for
(m, 2H, 2CH, conformer B), 5.67 (s, 2H, 2CH, conformer A), 5.81
C17H22FNO4: C, 63.14; H, 6.86; N, 4.33%. Found: C, 63.12; H,
(s, 2H, 2CH, conformer C), 7.06–7.10 (m, 2H, CH), 7.35–7.39 (m, 6.84; N, 4.30%.
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6H, 3CH2), 1.42–1.44 and 1.63–1.67 and 1.80–1.85 (m, 4H,
2CH2), 5.67 (s, 2H, 2CH, conformer A), 5.80 (s, 2H, 2CH,
conformer B+C), 7.01–7.03 (m, 2H, 2CH, conformer A), 7.10–
7.15 (m, 2H, 2CH, conformer B+C), 6.96–6.97 (m, 2H, 2CH,
conformer B+C), 7.19–7.27 (m, 2H, 2CH, conformer A). 13C NMR
(125.78 MHz, CDCl3, 25 ꢁC): d ¼ 14.6 (conformer A), 16.3
(conformer B+C), 22.0 (conformers B+C), 22.3 (conformer A),
22.1, 26.4 (conformer A), 26.6 (conformer B+C), 31.2 (conformer
A), 31.4 (conformer B+C), 86.0 (conformer B+C), 86.9
(conformer A), 111.1, 119.0 (conformer A), 119.8 (conformer
B+C), 124.5, 128.7 (conformers A), 129.0 (conformers B+C),
144.8. MALDI TOF/TOF, m/z: 366 [M ꢂ H]+. Anal. calcd for
11-(3-Fluorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclohexane] 12c
Brown oil; 0.24 g (75% yield), Rf 0.81 (PE/Et2O ¼ 10/1). 1H NMR
(500.17 MHz, CDCl3, 25 ꢁC): d ¼ 1.31–1.46 (m, 4H, CH2, 2CHa),
1.48–1.62 (m, 5H, 2CH2, CHa), 1.72–1.99 (m, 4H, 2CH2), 2.14–
2.19 (m, 1H, CHb), 2.22–2.25 (m, 2H, CHb), 5.37–5.39 (m, 2H,
2CH, conformer C), 5.69 (br.s, 2H, 2CH, conformer A), 5.85–5.86
(m, 2H, 2CH, conformer B), 6.59–6.68 (m, 1H, CH), 6.89–6.98
(m, 2H, CH), 7.15–7.25 (m, 1H, CH). 13C NMR (125.78 MHz,
CDCl3, 25 ꢁC): d ¼ 14.2 (conformer B+C), 14.6 (conformer A),
21.0 (conformers B+C), 22.0 (conformer A), 22.5 (conformer B),
22.7 (conformer A), 22.8 (conformer C), 25.0 (conformer C), 25.3
(conformer B), 25.4 (conformer A), 26.4 (conformer A), 26.9
(conformer C), 27.0 (conformer B), 85.6 (conformer B), 86.7
(conformer C), 86.9 (conformer A), 104.8 (J ¼ 17, conformer C),
105.3 (J ¼ 20, conformer B), 105.9 (J ¼ 20, conformer A), 107.2 (J
¼ 17 conformer A), 107.8 (J ¼ 17, conformers B+C), 108.8
(conformers B+C), 109.5 (conformer A), 113.3 (conformers B+C),
114.0 (conformer A), 129.7 (J ¼ 8, conformers A), 129.9 (J ¼ 7,
conformer B), 130.4 (J ¼ 8, conformer C), 151.3 (J ¼ 8,
conformers B+C), 151.8 (J ¼ 8, conformer A), 163.3 (J ¼ 194).
C
19H26ClNO4: C, 62.04; H, 7.12; N, 3.81%. Found: C, 62.02; H,
7.10; N, 3.79%.
11-(2-Chlorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclooctane] 14g
Orange solid; 0.27 g (74% yield), Rf 0.74 (PE/Et2O ¼ 10/1), mp
1
ꢁ
ꢁ
98–100 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 1.46–1.51
(m, 1H, CHa), 2.09–2.19 (m, 1H, CHb), 1.38–1.69 (m, 4H, 2CH2),
2.34–2.36 and 1.38–1.50 (m, 2H, 2CH2), 1.29–1.84 (m, 6H,
3CH2), 1.34–1.40 (m, 4H, 2CH2), 5.61 (s, 2H, 2CH, conformer A),
5.75 (s, 2H, 2CH, conformer B+C), 6.45–6.47 (m, 1H, CH), 6.58–
6.59 (m, 1H, CH), 6.62–6.63 (m, 1H, CH), 6.95–7.19 (m, H, CH).
MALDI TOF/TOF, m/z: 322 [M
17H22FNO4: C, 63.14; H, 6.86; N, 4.33%. Found: C, 63.11; H,
6.85; N, 4.32%.
ꢂ
H]+. Anal. calcd for
C
13
ꢁ
C NMR (125.78 MHz, CDCl3, 25 C): d ¼ 14.2 (conformer A),
16.1 (conformer B+C), 22.0 (conformers A), 22.3 (conformer
B+C), 24.7 (conformer A), 25.1 (conformer B+C), 25.7, 31.0
(conformer B+C), 31.4 (conformers A), 85.8 (conformer B), 86.7
(conformer C), 86.7 (conformer A), 113.3, 112.5 (conformer A),
113.2 (conformer B+C), 114.7, 117.9 (conformers A), 118.2
(conformers B+C), 129.7 (conformers B+C), 130.3 (conformers
A), 134.3 (conformers B+C), 134.6 (conformers A), 147.4
(conformers B+C), 148.1 (conformers A). MALDI TOF/TOF, m/z:
366 [M ꢂ H]+. Anal. calcd for C19H26ClNO4: C, 62.04; H, 7.12; N,
3.81%. Found: C, 62.01; H, 7.09; N, 3.79%.
11-(2-Chlorophenyl)-40-methyl-2,3,5,6-tetraoxa-11-azaspiro
[bicyclo[5.3.1]undecane-4,10-cyclohexane] 13f
Orange oil; 0.27 g (78% yield), Rf 0.76 (PE/Et2O ¼ 10/1). 1H NMR
ꢁ
(500.17 MHz, CDCl3, 25 C): d ¼ 0.97 (d, 3H, J ¼ 10 Hz, CH3,
conformer A), 1.04 (d, 3H, J ¼ 10 Hz, CH3, conformer B+C), 1.58–
1.59 and 2.21–2.28 (m, 2H, CH2), 1.89–1.92 and 2.14–2.19 (m,
4H, 2CH2), 1.59–1.61 and 3.09–3.11 (m, 4H, CH2), 1.23–1.73 (m,
4H, 2CH2), 1.98–2.03 (m, 1H, CH), 5.03–5.52 (m, 2H, 2CH), 6.69–
6.78 (m, 2H, 2CH), 6.97–7.40 (m, 2H, 2CH). 13C NMR (125.78
ꢁ
MHz, CDCl3, 25 C): d ¼ 14.2 (conformer C), 15.0 (conformers
A), 16.6 (conformer B), 21.6 (conformer A), 21.0 (conformers
B+C), 25.9 and 26.0 and 26.7 (conformers A+B+C), 30.9 and 31.2
(conformer B+C), 31.0 (conformers A), 31.4 (conformers B+C),
31.5 (conformer A), 31.7 and 31.9 (conformers B+C), 31.7
(conformer A), 34.8, 89.7 (conformer A), 89.6 and 89.8 and 89.9
(conformer A+B+C), 109.6, 113.7 (conformers B+C), 115.9
(conformers A), 119.0 (conformer A), 119.3 and 119.4
(conformers B+C), 127.4 and 127.6 and 127.8 (conformers B+C),
127.6 (conformers A), 129.2 (conformers B+C), 129.4
(conformers A), 130.2 (conformers B+C), 130.5 (conformer A),
143.0 (conformer B+C), 147.1 (conformer A), MALDI TOF/TOF,
m/z: 322 [M ꢂ H]+. Anal. calcd for C18H24ClNO4: C, 61.10; H,
6.84; N, 3.96%. Found: C, 61.08; H, 6.82; N, 3.94%.
11-(2-Chlorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclododecane] 15a
Orange crystal; 0.33 g (79% yield), Rf 0.78 (PE/Et2O ¼ 10/1), mp
1
ꢁ
ꢁ
82–84 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 1.27–1.36
(m, 12H, 6CH2), 1.70–1.75 (m, 2H, CH2), 1.27–1.98 (m, 4H,
2CH2), 2.15–2.20 and 1.98–2.20 (m, 4H, 2CH2), 2.15–2.41 (m,
2H, CH2), 5.35–5.36 (m, 2H, 2CH, conformer B), 5.66 (s, 2H,
2CH, conformer A), 5.82 (s, 2H, 2CH, conformer C), 7.03–7.08
(m, 1H, CH), 7.15–7.21 (m, 2H, CH), 6.87–6.94 (m, 1H, CH). 13
C
ꢁ
NMR (125.78 MHz, CDCl3, 25 C): d ¼ 14.2 (conformer A), 16.1
(conformer B+C), 22.0 (conformers A), 22.3 (conformer B+C),
24.7 (conformer A), 25.1 (conformer B+C), 25.7, 31.0 (conformer
B+C), 31.4 (conformers A), 85.8 (conformer B), 86.7 (conformer
C), 86.7 (conformer A), 113.3, 112.5 (conformer A), 113.2
(conformer B+C), 114.7, 117.9 (conformers A), 118.2
(conformers B+C), 129.7 (conformers B+C), 130.3 (conformers
11-(2-Chlorophenyl)-2,3,5,6-tetraoxa-11-azaspiro[bicyclo[5.3.1]
undecane-4,10-cyclooctane] 14a
Orange oil; 0.26 g (70% yield), Rf 0.77 (PE/Et2O ¼ 10/1). 1H NMR A), 134.3 (conformers B+C), 134.6 (conformers A), 147.4
ꢁ
(500.17 MHz, CDCl3, 25 C): d ¼ 1.56–1.59 (m, 1H, CHa), 2.14– (conformers B+C), 148.1 (conformers A). MALDI TOF/TOF, m/z:
2.15 (m, 1H, CHb), 1.63–1.67 and 1.51–1.53 (m, 4H, 2CH2), 2.38– 366 [M ꢂ H]+. Anal. calcd for C23H34ClNO4: C, 65.16; H, 8.08; N,
2.40 (m, 2H, 2CH2), 2.17–2.24 and 1.95–2.00 and 1.77–1.87 (m, 3.30%. Found: C, 65.12; H, 8.06; N, 3.28%.
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TOF/TOF, m/z: 205 [M ꢂ H]+. Anal. calcd for C8H14O6: C, 46.60;
11'-(3-Chlorophenyl)-20,30,50,60-tetraoxa-110-azaspiro
[adamantane-2,40-bicyclo[5.3.1]undecane] 16g
H, 6.84%. Found: C, 46.58; H, 6.81%.
Brown oil; 0.28 g (72% yield), Rf 0.80 (PE/Et2O ¼ 10/1). 1H NMR
ꢁ
3-Methyl-7,8,11,12-tetraoxaspiro[5.6]dodecane-9,10-diol 20
(400 MHz, CDCl3, 25 C): d ¼ 1.66–1.74 (m, 2H, CH2-Ad), 1.77
(m, 1H, CH-Ad, conformer A), 1.82–1.86 (m, 8H, CH2-Ad), 1.95–
2.01 (m, 4H, CH2-Ad, conformer A), 2.04–2.06 (m, 4H, CH2-Ad),
2.10–2.17 (m, 4H, 2CH2), 2.19–2.28 (m, 2H, CH2), 2.31 (br.s, 2H,
CH2-Ad), 2.39 (br.s, 1H, CH2-Ad, conformer A), 5.48–5.49 (m,
2H, 2CH, conformer B), 5.68 (s, 2H, 2CH, conformer A), 5.81 (s,
2H, 2CH, conformer C), 6.77–6.84 (m, 1H, CH), 6.89–6.95 (m,
1H, CH), 7.02–7.13 (m, 1H, CH), 7.15–7.23 (m, 1H, CH). 13C
NMR (100 MHz, CDCl3, 25 ꢁC): d ¼ 14.6 (conformer A), 16.3
(conformer B+C), 26.5, 27.1 (conformer B+C), 27.2 (conformer
A), 30.3, 33.1 (conformer A), 33.6 (conformer B+C), 34.2
(conformers B+C), 34.4 (conformer A), 37.3 (conformer B+C),
37.4 (conformer A), 84.8 (conformer B), 86.1 (conformer C), 86.9
(conformer A), 110.9 (conformer B), 111.5 (conformer A), 112.6
(conformer C), 116.6 (conformers B+C), 116.9 (conformer A),
118.8 (conformers A), 119.1 (conformers B+C), 120.5 (conformer
A), 121.4 (conformers B+C), 129.7, 151.3. MALDI TOF/TOF, m/z:
390 [M ꢂ H]+. Anal. calcd for C21H26ClNO4: C, 64.36; H, 6.69; N,
3.57%. Found: C, 64.33; H, 6.67; N, 3.55%.
White solid; 0.18 g (85% yield), Rf 0.76 (PE/Et2O ¼ 10/1), mp ¼
1
ꢁ
ꢁ
68–70 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 0.91–0.93
(m, 3H, CH3), 1.30–1.46 (m, 4H, CH2), 1.61–1.62 (m, 4H, CH2),
1.98–2.03 (m, 1H, CH) 5.20–5.35 (m, 2H, 2CH). 13C NMR (125.78
ꢁ
MHz, CDCl3, 25 C): d ¼ 20.5, 22.6, 22.7, 25.0, 25.2, 31.2, 31.6,
32.0, 32.7, 90.3, 91.2, 113.5. MALDI TOF/TOF, m/z: 219 [M ꢂ H]+.
Anal. calcd for C9H16O6: C, 49.09; H, 7.32%. Found: C, 49.07; H,
7.30%.
Crystal structure determination and renement
The crystallographic data, coordinates of atoms, and geometric
parameters for compounds 4a, 4b, 4d, 4e, 12b were deposited at
the Cambridge Crystallographic Data Centre as a CIF deposition
with le number CCDC 1905323, 1905327, 1905330, 1905341,
1905334, 1905337, respectively.
Crystal data for 4b. Crystals of C20H22F2N2O4 (M ¼ 392.40)
are monoclinic, space group P21/c, a ¼ 18.9061(6), b ¼
ꢁ
ꢀ
11.4711(4) and c ¼ 8.7831(3) A, b ¼ 99.134(3) , V ¼ 1880.66(11)
A , dcalc ¼ 1.386 g cmꢂ3, Z ¼ 4, m ¼ 0.110 mmꢂ1, 2qmax
¼
ꢀ3
Cyclocondensation reactions of gem-dihydroperoxides with
glyoxal catalyzed by Sm(NO3)3$6H2O
58.302ꢁ, 9078 reections were measured, from which 4395 were
independent. The renement converged to R1 ¼ 0.0544, wR2 ¼
0.1617, GOF ¼ 1.030.
General procedure: a Schlenk vessel mounted on a magnetic
stirrer was charged at ꢀ20 ꢁC with tetrahydrofuran (5 ml),
glyoxal (10 mmol), and specied gem-dihydroperoxides (10
mmol).29 Then Sm(NO3)2$6H2O (0.062 g, 5 mol% relative to 1,10-
peroxybis(1-hydroperoxycyclꢁoalkane)) was added. The reaction
mixture was stirred at ꢀ20 C for 1 h. Aer completion of the
reaction H2O (5 ml) and CH2Cl2 (5 ml) were added. The organic
layer was separated, dried (anhydrous MgSO4) and concentrated
to isolate products stable during storage at room temperature.
Products of the reaction were puried by column chromatog-
raphy on SiO2 using 10 : 1 PE : Et2O as the eluent. The progress
of reactions was monitored by TLC, with a 5 : 1 hexane : EtOAc
mixture as the eluent, visualization was performed with I2
vapor.
Crystal data for 4a. Crystals of C20H22Cl2N2O4 (M ¼ 425.30)
are monoclinic, space group P21/n, a ¼ 10.5362(9), b ¼ 9.4705(6)
ꢀ3
ꢁ
ꢀ
and c ¼ 20.3165(17) A, b ¼ 99.462(8) , V ¼ 1999.7(3) A , dcalc
¼
1.413 g cmꢂ3, Z ¼ 4, m ¼ 0.354 mmꢂ1, 2qmax ¼ 58.562ꢁ, 13 245
reections were measured, from which 4644 were independent.
The renement converged to R1 ¼ 0.0608, wR2 ¼ 0.1916, GOF ¼
0.987.
Crystal data for 4d. Crystals of C20H22F2N2O4 (M ¼ 392.40)
are monoclinic, space group P21/n, a ¼ 12.9687(13), b ¼
ꢁ
ꢀ
10.0294(8) and c ¼ 14.5182(15) A, b ¼ 100.068(10) , V ¼
1859.3(3) A , dcalc ¼ 1.402 g cmꢂ3, Z ¼ 4, m ¼ 0.111 mmꢂ1, 2qmax
ꢀ3
¼ 58.232ꢁ, 9607 reections were measured, from which 4313
were independent. The renement converged to R1 ¼ 0.0825,
wR2 ¼ 0.2015, GOF ¼ 1.026.
Crystal data for 4e. Crystals of C20H22Br2N2O4 (M ¼ 514.20)
are monoclinic, space group P21/n, a ¼ 10.6640(6), b ¼ 9.4362(6)
6,7,10,11-Tetraoxaspiro[4.6]undecane-8,9-diol 18
White solid; 0.16 g (82% yield), Rf 0.79 (PE/Et2O ¼ 10/1), mp ¼
ꢀ3
ꢁ
ꢀ
and c ¼ 20.7558(11) A, b ¼ 97.997(5) , V ¼ 2068.3(2) A , dcalc
¼
1
ꢁ
ꢁ
96–98 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 1.72–1.80
(m, 4H, CH2) 1.90–2.04 (m, 4H, CH2), 5.15–5.22 (m, 2H, 2CH).
13C NMR (125.78 MHz, CDCl3, 25 ꢁC): d ¼ 24.2, 24.3, 33.5, 33.7,
90.9, 91.1, 110.4. MALDI TOF/TOF, m/z: 191 [M ꢂ H]+. Anal.
calcd for C7H12O6: C, 43.75; H, 6.29%. Found: C, 43.73; H,
6.27%.
1.651 g cmꢂ3, Z ¼ 4, m ¼ 3.948 mmꢂ1, 2qmax ¼ 58.354ꢁ, 9852
reections were measured, from which 4798 were independent.
The renement converged to R1 ¼ 0.0749, wR2 ¼ 0.1777, GOF ¼
0.986.
Crystal data for 12b. Crystals of C17H22FNO4 (M ¼ 323.36) are
ꢁ
triclinic, space group P1, a ¼ 6.4738(3), b ¼ 10.2056(9) and c ¼
ꢁ
ꢁ
ꢁ
ꢀ
ꢀ3
12.4931(10) A, a ¼ 75.029(7) , b ¼ 80.670(6) , g ¼ 88.090(6) , V ¼
786.81(11) A , dcalc ¼ 1.365 g cmꢂ3, Z ¼ 2, m ¼ 0.104 mmꢂ1
,
7,8,11,12-Tetraoxaspiro[5.6]dodecane-9,10-diol 19
White solid; 0.17 g (85% yield), Rf 0.76 (PE/Et2O ¼ 10/1), mp ¼ 2qmax ¼ 58.558ꢁ, 6406 reections were measured, from which
1
ꢁ
ꢁ
54–56 C. H NMR (500.17 MHz, CDCl3, 25 C): d ¼ 1.46–1.47 3602 were independent. The renement converged to R1
(m, 4H, CH2), 1.59–1.64 (m, 2H, CH2), 1.88–1.90 (m, 4H, CH2) 0.0472, wR2 ¼ 0.1235, GOF ¼ 1.022.
¼
13
ꢁ
5.27–5.33 (m, 2H, 2CH). C NMR (125.78 MHz, CDCl3, 25 C):
Crystal data for 19. Crystals of C8H14O6 (M ¼ 206.19) are
d ¼ 22.5, 22.6, 25.2, 25.4, 29.8, 30.7, 90.5, 91.0, 113.5. MALDI orthorhombic, space group Pbca, a ¼ 6.5986(6), b ¼ 9.8591(8)
29956 | RSC Adv., 2019, 9, 29949–29958
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ꢀ3
ꢁ
ꢁ
ꢁ
ꢀ
and c ¼ 29.604(2) A, a ¼ 90 , b ¼ 90 , g ¼ 90 , V ¼ 1925.9(3) A ,
9 K. Sun, Z. Liu, B. Luan, J. Zhu and Y. Xue, Org. Lett., 2018, 20,
6687.
dcalc ¼ 1.422 g cmꢂ3, Z ¼ 8, m ¼ 0.123 mmꢂ1, 2qmax ¼ 58.102ꢁ,
4693 reections were measured, from which 1905 were inde- 10 X. Huang, N. Rong, P. Li, G. Shen, Q. Li, N. Xin, C. Cui, J. Cui,
pendent. The renement converged to R1 ¼ 0.0953, wR2
¼
B. yang, D. Li, C. Zhao, J. Dou and B. Wang, Org. Lett., 2018,
20, 3332.
11 C. Wu, X. Xin, Z.-M. Fu, L.-Y. Xie, K.-J. Liu, Z. Wang, W. Li,
Z.-H. Yuan and W.-M. He, Green Chem., 2017, 19, 1983.
12 L.-H. Lu, Z. Wang, P. Cheng, B. Zhang, Z. Cao and W.-M. He,
Chin. Chem. Lett., 2019, 20, 1237.
0.2238, GOF ¼ 0.980.
Conflicts of interest
There are no conicts to declare.
13 J. Fayos, D. Lokensgard, J. Clardy, R. J. Cole and
J. W. Kirksey, J. Am. Chem. Soc., 1974, 96, 6785.
Acknowledgements
14 R. J. Cole, J. W. Kirsey, J. W. Dorner, D. M. Wilson, J. Johnson
Jr, N. Johnson, D. M. Dedell, J. P. Springer, K. K. Chexel,
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This work was nancially supported by the Russian Science
Foundation (RSF projects 18-73-00014). The structural studies
of the synthesized compounds were performed with the use of
Collective Usage Centre “Agidel” at the Institute of Petrochem-
istry and Catalysis of RAS. The anticancer activity studies of the
synthesized compounds were performed in laboratory of
molecular design and biological screening of candidate
substances for the pharmaceutical industry at the Institute of
Petrochemistry and Catalysis of RAS.
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N.
Makhmudiyarova,
G.
M.
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R. Sh. Rakhimov, A. G. Ibragimov and U. M. Dzhemilev,
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