Synthesis, molecular structure, conformation and biological activity of Ad-substituted N-aryl-tetraoxaspiroalkanes

Article abstract of DOI:10.1016/j.tet.2018.01.045

An efficient method has been developed for the synthesis of 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)} by the ring transformation reaction of spiro{adamantane-[2,3’]-(1′,2′,4′,5′,7′-pentaoxacane)} with arylamines in the presence of S

Full text of DOI:10.1016/j.tet.2018.01.045

Accepted Manuscript
Synthesis, molecular structure, conformation and biological activity of Ad-substituted
N-aryl-tetraoxaspiroalkanes
Tatyana V. Tyumkina, Nataliya N. Makhmudiyarova, Guzeliya M. Kiyamutdinova,
Ekaterina S. Meshcheryakova, Kamil Sh. Bikmukhametov, Marat F. Abdullin, Leonard
M. Khalilov, Askhat G. Ibragimov, Usein M. Dzhemilev
PII:
S0040-4020(18)30093-0
10.1016/j.tet.2018.01.045
TET 29260
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 November 2017
Revised Date: 19 January 2018
Accepted Date: 25 January 2018
Please cite this article as: Tyumkina TV, Makhmudiyarova NN, Kiyamutdinova GM, Meshcheryakova
ES, Bikmukhametov KS, Abdullin MF, Khalilov LM, Ibragimov AG, Dzhemilev UM, Synthesis, molecular
structure, conformation and biological activity of Ad-substituted N-aryl-tetraoxaspiroalkanes, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.01.045.
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ACCEPTED MANUSCRIPT
GraphicalAbstract
Synthesis, Molecular Structure, Conformation and
Biological Activity of Ad-substituted
N-Aryl-tetraoxaspiroalkanes
Tatyana V. Tyumkinaa, Nataliya N. Makhmudiyarovaa, Guzeliya M. Kiyamutdinovaa, Ekaterina S.
Meshcheryakovaa, Kamil Sh. Bikmukhametova, Marat F. Abdullinb, Leonard M. Khalilova, Askhat G.
Ibragimova and Usein M. Dzhemileva
aInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141
prospekt Oktyabrya, 450075 Ufa, Russian Federation
bUfa Institute of Chemistry, Russian Academy of Sciences, 71 prospekt Oktyabrya, 450054 Ufa, Russian
Federation
3

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Synthesis, Molecular Structure, Conformation and Biological Activity
of Ad-substituted N-Aryl-tetraoxaspiroalkanes
Tatyana V. Tyumkinaa*, Nataliya N. Makhmudiyarovaa, Guzeliya M.
Kiyamutdinovaa, Ekaterina S. Meshcheryakovaa, Kamil Sh. Bikmukhametova, Marat F.
Abdullinb, Leonard M. Khalilova, Askhat G. Ibragimova and Usein M. Dzhemileva
aInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141
prospekt Oktyabrya, 450075 Ufa, Russian Federation
bUfa Institute of Chemistry, Russian Academy of Sciences, 71 prospekt Oktyabrya,
450054 Ufa, Russian Federation
Abstract
An efficient method has been developed for the synthesis of 7′-
arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)}
by
the
ring
transformation reaction of spiro{adamantane-[2,3’]-(1′,2′,4′,5′,7′-pentaoxacane)}
with arylamines in the presence of Sm(NO3)3·6H2O as the catalyst. NMR signals of
the synthesized compounds were assigned considering the conformation dynamics
of the tetraoxazocane ring with two rigid peroxide bonds. The structures of some of
the compounds were studied by X-ray diffraction. The thermal stability of single
crystal
was
determined
by
DSC
method.
Compounds
7′-(2-
methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} and 7′-(4-
fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)}
exhibited
cytotoxicity towards cancer cells.
Key words
catalysis, ring transformation, arylamines, Ad-substituted pentaoxaspiroalkanes, N-
aryltetraoxazaspiroalkanes, conformation, multicomponent conformational
equilibrium, X-ray diffraction, variability of peroxide bond lengths, cytotoxicity.
* Corresponding author. E-mail address: ttvnmr@gmail.com (T.V. Tyumkina)

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Introduction
Studies of peroxides represent a topical task owing to the important role they play in
oxidation processes and light generation mechanisms in chemical and biochemical
systems and to their wide use in organic synthesis and medicine.1 The past decades can be
rightfully termed the renaissance of the organic peroxide chemistry, which is related to
the development of pharmaceutical drugs based on the natural trioxane, artemisinin,
which has an antimalarial 2a,d and anticancer activity 2b-d, and to the discovery of important
pharmacological properties in synthetic 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes.2 In
2012, a synthetic trioxolane, Arterolane (OZ277),3,4 became a part of the Synriam
antimalarial drug (Ranbaxy company), and the tetraoxane RKA182 was recently selected
for clinical trials.5 It is noteworthy that apart the antimalarial properties, tetraoxanes were
found to exhibit antitumor and anthelmintic activities. Although the mechanism of
antimalarial activity still remains open, it was found that the key role in this process
belongs to the interaction of iron(II) with the peroxide bond.6
Currently, a lot of attention is paid to studies of stability, reactivity,
pharmacokinetics, and the mechanism of action of biologically active peroxides and to
the synthesis of new derivatives. The antimalarial activity is considerably enhanced by
the presence of an adamantane substituent and nitrogen-containing (amino or amido)
basic groups in the molecule.7-9 Indeed, the molecules of known antimalarial agents of
both synthetic10 and natural (verruculogen11a or dioxetanone11b) origin incorporate the
nitrogen-containing peroxide -N-CH2-O-O- moiety. In this connection, of considerable
interest from the biological activity standpoint are N-containing cyclic peroxides,12 which
remain poorly studied, since they are difficult to synthesize and only few methods for
their synthesis are available.10,12,13 Thermal stability is also an important issue for amino
peroxides.
In view of the above, we suggested that Ad-substituted N-aryl-tetraoxaspiroalkanes
combining the necessary pharmacologically active groups in the molecule could be of
considerable interest as potential antimalarial agents. The target compounds were
synthesized using the approach proposed in our earlier works, which is based on ring
transformation of pentaoxaspiroalkanes with arylamines.14 The first synthesis of N-aryl-
substituted tetraoxazaspiroalkanes was accomplished by this method.14

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Thus, our goal was to develop a catalytic method for the selective synthesis of Ad-
substituted N-aryl-tetraoxazaspiroalkanes and to study the structure and conformations of
the resulting heterocyclic compounds. Despite the fact that the conformational behavior
of compounds considerably affects their biological activity, there are only few
publications devoted to the conformational analysis of heteroatom-containing
peroxides.15,16 Furthermore, the spectral parameters of cyclic compounds depend not only
on isomerism, but also on the conformational state of the ring; therefore, conformational
analysis is exceptionally important for reliable identification of new Ad-substituted N-
aryl-tetraoxaspiroalkanes, which present interest for their biological activity. All
synthesized compounds were tested in vitro for anticancer activity.
Results and Discussion
The ring transformation reaction between the Ad-substituted pentaoxacanes and
primary amines catalyzed by Sm(NO3)3·6H2O made it possible to solve the problem of
selective synthesis of adamantyl-substituted cycloamino diperoxides. The choice of the
catalyst was due to its high activity in the synthesis of N-aryl-tetraoxazaspiroalkanes that
we described previously.14
In relation to the reaction of spiro{adamantane-[2,3’]-(1′,2′,4′,5′,7′-
pentaoxacane)}17 1 with о-fluoroaniline 2а, it was found that the reaction carried out in
the presence of Sm(NO3)3·6H2O (0.5 mol. %) as the catalyst for 6 h at ~ 20оС in THF
gives 7′-(о-fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} 3а in
.
95% yield. Under the chosen conditions (5 mol. % Sm(NO3)3 6H2O, 20оС, 6 h, THF),
aryl (m,p-fluorophenyl, o,m,p-chlorophenyl, o,m,p-methoxymethyl, o,m,p-methylphenyl)
amines 3b-i undergo ring transformation reaction with spiro{adamantane-[2,3’]-
(1′,2′,4′,5′,7′-pentaoxacane)} 1 to give 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-
tetraoxazocanes)} 3а-i in 80 – 99% yields.

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Scheme 1
Apart from arylamines, the catalytic ring transformation with spiro{adamantane-[2,3’]-
(1′,2′,4′,5′,7′-pentaoxacane)} 1 was carried out for aromatic diamines (o,m,p-
phenylenediamines). The ring transformation of compound 1 with p-phenylenediamine 4
.
under the developed conditions (5 mol.% Sm(NO3)3 6H2O, 20оС, 6 h, THF) also gives
rise to the target 4-spiro[adamantane-2,3'-[1,2,4,5,7]tetraoxazocane]-7'yl)aniline 5,
whereas the reaction with m–phenylenediamine affords a precipitate insoluble in organic
solvents and difficult to identify. It was found that spiro{adamantane-[2,3’]-(1′,2′,4′,5′,7′-
pentaoxacane)} 1 reacts with о-phenylenediamine 6 to give adamantanone 8 and 2H,5H-
1,6-(methanedioxymethano)benzo[e][1,2,4,7]-dioxazocine 7 (Scheme 2).
Scheme 2
The structures of 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)}
3b,d,h,i (Fig. 1) and 7 (Fig. 7) were reliably established by NMR spectroscopy and X-ray
diffraction.

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3b
3d
3h
3g
Figure 1. Molecular structure of compounds 3b, 3d, 3h, and 3g according to X-ray
diffraction data. The atoms are shown by thermal ellipsoids (р=50%).
According to the single crystal X-ray diffraction studies of compounds 3b, 3d, 3h,
and 3g have the molecular structure that is shown in Fig. 1. These compounds are
characterized by the presence of a common moiety, spiro[adamantane-2,2'-
[1,3,4,8,6]tetraoxazocane], in which the tetraoxazocane moiety has a distorted twist-chair
conformation. The N-aryl substituents occupy the axial position relative to the
tetraoxazocane ring plane. The О–О bond length in the tetraoxazocane moiety varies over
a broad range from 1.446 to 1.475 Å. (Table 1).
Table 1. О–О bond lengths from our and published data
Experimental data
3h 3b
Published data, Ref. code
Comp.
3g
3d
CEDDOE GUCLIA VIBHIX
[18]
Length, 1.466(3) 1.463(3) 1.475(3) 1.453(3) 1.476
[19]
[20]
1.477
1.471

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Å
1.446(3) 1.463(3) 1.458(4) 1.469(3) 1.476
1.476
1.471
According to published data for tetraoxane rings, the О–О bond lengths are in the
range of 1.471–1.477 Å (Table 1). In addition, the peroxide bonds in the tetraoxazocane
ring are nonequivalent in structures 3h, 3g and 3d. By considering the C–N and С–О
bond lengths in structures 3h, 3b, 3g, and 3d, one can follow the effect of substituent
(Table 2). The presence of halogens in the para-position of the aryl moiety decreases the
length of the exocyclic С–N bond and increases the endocyclic bond lengths in the
structures 3b and 3d, and the inverse relationship is observed for compounds 3h and 3g
(plot 1). The С–О bond lengths are minimized if the methyl group occurs in the para-
position of the aromatic ring (Table 2, plot 1).
Table 2. Selected bond lengths, Å.
Bond length
Compounds
(N)С–О
С–N(endo)
C–N(exo)
1.427(5)
1.411(4)
1.422(4)
1.405(5)
1.429(4)/1.428(5)
1.437(4)/1.442(4)
1.448(4)/1.440(4)
1.448(7)/1.430(6)
1.417(6)/1.419(5)
1.426(4)/1.422(3)
1.419(3)/1.419(4)
1.420(7)/1.426(7)
3h
3b
3g
3d
Figure 2. Ratio of the exo- and endocyclic С–N bond lengths and С–О bond lengths.
Thus, eight-membered amino peroxide ring derivatives crystallize in the twist-chair
ring conformation.

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However, we found that at room temperature in solution, a multicomponent
equilibrium occurs between conformations with different spatial ring arrangements. For
example, the 1H and 13C NMR spectra for the series of compounds contain a double set of
hydrogen and carbon signals for the whole molecule. The signal intensities in each pair
1
considerably differ, their ratio being about 1 : 2.5 in the H NMR spectra, for example,
for the methylene protons of the characteristic N-CH2 groups (Fig. 3). As can be seen
from Fig. 3, these diastereotopic protons in compound 3b in chloroform and toluene
solutions exhibit two pairs of doublets, particularly, the relatively low-field doublets at
5.09 ppm and 5.17 ppm with a geminal constant of 14.5 Hz, which are correlated with the
minor 13С signal at δ = 88.9 ppm according to HSQC data, and doublets at 4.83 ppm and
4.96 ppm with 2J=10.0 Hz, correlated with the major carbon signal at 86.2 ppm (Fig. 3а).
The above-mentioned signals of the latter pair of doublets are clearly broadened, which
evidently attests to conformational exchange and averaging of NMR spectral parameters
on the NMR time scale. Indeed, at the coalescence temperature Т = 243 K, these doublets
are split into two doublets of doublets, and at 208 K three conformers can be observed
separately (Fig. 3е).
A
С
e
B
d
c
b
B+C
A
-N-CH2-
a

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Figure 3. Fragment of the 1Н NMR spectrum of compound 3b in toluene at (а)
298 K, (b) 263 K, (c) 252 K, (d) 238 K, (e) 208 K. The assignment of signals for the
conformer B or conformers (B+Bʹ) is made.
In order to determine the structures of the conformers and also in view of the
lack of literature data about the conformational behavior of this class of compounds,
the potential energy surface (PES) of 7′-phenyl-spiro{adamantane-[2,3′]-
(1′,2′,4′,5′,7′-tetraoxazocane)}, as model for 3b compound, we investigated by the
B3LYP quantum chemical method in the 6-31G(d,p) basis set for the gas phase
(Gaussian 09 program). The stable conformations of the eight-membered N,O-
heterocycle corresponding to the minima in the PES of the molecule are the chair-
chair А, twist-chair B and chair-boat C structures; for the twist-form conformer Bʹ
is also identified, which is located in the PES somewhat higher in energy and differs
in the dihedral angles of the oxazocane ring. (Fig. 4). It was found that conformers
А and B, which are close in energy, are the most favorable, the latter being
crystallized in the solid phase.
А 0.0 kcal/mol
B 0.1 kcal/mol

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Bʹ 1.2 kcal/mol
С 2.4 kcal/mol
Figure 4. Stable conformations of the 7′-phenyl-spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-
tetraoxazocane)}
Thus, the energy differences between the adamantane peroxide conformers are
small, within 1.2 kcal/mol; however, the barriers for their interconversion are
sufficiently high. Indeed, the coalescence of signals of the conformer observable at
room temperature does not occur in the 298‒340 K range, obviously due to the
absence of low-energy pathways for conformational transitions (∆G≠ ˃ 17.0
1
13
kcal/mol). Comparative analysis of the H and C NMR spectra of a mixture of
conformers with markedly different signal intensities of components was used to
identify conformer А. Only in this chair-chair conformation, the 2-spiro-substituted
adamantane and N-aromatic moieties of the amino peroxide 3b molecule are
spatially proximate, for example, the calculated distance between one β-methine
proton and the para-proton of the benzene ring is d = 2.8 Å. This ring configuration
enables observation of the NOE effect: the NOESY spectrum was found to exhibit a
cross-peak between the signal at 3.0 ppm and the multiplet in the aromatic region,
which is less intense and is located in a lower field than that for other conformers.
Evidently, the considerable shift of the βsyn-proton signal is caused by the
deshielding effect of the p-substituted phenyl substituent.21 Simultaneously, the
signal at δC 30.8 ppm of the carbon atom bound to this proton is in a higher field
than the βanti carbon of adamantane.
δH2.0 ppm
δC 34.8 ppm
δC 30.8 ppm
NOE
δH 3.0 ppm
Figure 5. NMR signals assignment for conformer А based on NOESY data

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Thus, from the shifts of NMR signals, βanti-CH and βsyn-CH (∆δC = 4.0 ppm, ∆δH =
1.0 ppm), we found the spectral criteria for the assignment of conformer А in the 7′-(N-
aryl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} 3b. It is noteworthy that in
the 13С NMR spectra of 2-substituted adamantane derivatives, only the δanti and δsyn
carbon atoms are sensitive to the substituent configuration.22 As a result, we made
complete assignment of the 1H and 13С NMR signals corresponding to conformer А, and
found that 13С NMR signals of the heterocycle are shifted downfield with respect to those
of conformations B and C both at room temperature and at 208 K. The experimental
results are consistent with the theoretical data, because the relative chemical shifts
calculated for the carbon atoms of the tetraoxacane ring in three conformations are
correlated with our assignments (Table 3).
13
Table 3. Calculated and experimental С NMR chemical shifts of conformers А,
B, and C of compound 3b.
СH2calc
96.9
92.4
СH2exp
88.6
85.3
Ccalc
126.9
122.9
124.5
Cexp
113.2
110.5
110.5
А
В
С
93.3
85.8
As follows from Table 6, the -N-CH2-O signal of the ring of twist-conformer В
should be located in the highest field. Therefore, the signal at 85.3 ppm, which is HSQC-
correlated with methylene proton signals with markedly different chemical shifts (∆δ =
2
1.10 ppm) and with the geminal constant JA = 9.5 Hz, was assigned to this conformer
(Fig. 3e). The diastereotopic nature of the corresponding protons in the other two
conformers, which represent a combination of classical chair and boat conformations, is
less pronounced (∆δ ~ 0.10 ppm), and the geminal constants for both conformers are also
2
similar (2JA = 14.5 Hz, JC = 14.1 Hz). Good agreement between the calculated and
experimental chemical shifts is, obviously, due to the rigidity of the structures; therefore,
we also performed signal assignment for the adamantane moiety in the three
conformation states in relation to compound 3b as an example (Fig. 6).

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A C B
c
b
A,Cβ-
syn
A,Cβ-anti
-Ad
B+C
A
-N-CH2-O-
a
13
Figure 6. Fragment of the С NMR spectrum of compound 3b in toluene at (а)
298 K, ( b) 233 K, (c) 208 K
Direct interconversion of conformations A and C of the eight-membered ring does
not take place in solution, but can occur only via the twist form, with the activation
barrier for the A ↔ B transition being rather high (∆G≠ ˃ 17 kcal/mol). The B ↔ С
transitions occur at room temperature, because the barrier determined experimentally by
13
full line shape analysis in the С NMR spectra (Fig. 6b) is lower, namely, ∆G≠ = 12.2
(±0.1) kcal/mol.
Thus, at room temperature, amino peroxides represent the first example of
multicomponent equilibrium between the chair-chair А, chair-boat С and twist-boat В
conformers of eight-membered heterocycles, with the ratio of 0.8 : 1 : 1 at 208K,
respectively.
Note that in the known Mannich reaction conditions,23 no target 7′-
arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)} 3b-i are formed. Three-
component condensation of 2,2′-dihydroperoxyadamantane 9 with formaldehyde and
aromatic amines yielded triazines 10a-i and ((2-hydroperoxyadamantan-2-
yl)peroxy)methanol 11 in 1:2 ratio (Scheme 3).
Scheme 3

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The structures of ((2-hydroperoxyadamantan-2-yl)peroxy)methanol 11 and
2H,5H-1,6-(methanedioxymethano)benzo[e][1,2,4,7]dioxazocine 7 were confirmed
by X-ray diffraction.
The structures of ((2-hydroperoxyadamantan-2-yl)peroxy)methanol 11 and
2H,5H-1,6-(methanedioxymethano)benzo[e][1,2,4,7]dioxazocine 7 based on single
crystal X-ray diffraction analysis are presented in Fig. 7.
11
7
Figure 7. Molecular structure of compounds 11 and 7 from X-ray diffraction data. The
atoms are shown by thermal ellipsoids (р=50%).
The geometric parameters of the adamantane moiety of compound 11 correspond
to those of unsubstituted adamantane. The О–О bond lengths are 1.478 and 1.461Å. An
intramolecular hydrogen bond with a 1.967Å length is present. The crystal structure of
tricyclic peroxide 7 was determined previously by researchers from the California
Institute of Technology.24 The average О–О bond length in compound 7 is 0.027 Å
shorter than the reported value. As in the known structure, in this case, too, the О(16) and
О(15) oxygen atoms are disordered. The nitrogen atom has a planar conformation.
Atmospheric pressure chemical ionization (APCI) mass spectra of investigated
compounds 3b,c,e-h and 5 contain peaks of the specific fragment ions [C7H6FN+H]+,
[C7H6ClN+H]+, [C8H9N+H]+, [C8H9NO+H]+, [C9H11NO+H]+, [C9H11NO4+H]+,
[C8H10N2O+H]+, [C8H10N2O2+H]+ and corresponding [M+H+CH3CN]+ ions of ion-
solvent associates (see experimental section). Ions [C8H9N+H]+ and [C8H9NO+H]+
emerge in mass spectra of the compounds 3e, 3f and 3h.
For estimating the thermal stability of the products the differential scanning
calorimetry (DSC) data were obtained for compounds 3i (SI, Fig 27), that demonstrate
the thermal stability of the synthesized cyclic aminoperoxide up to 100.1 °C. There is the

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exothermic peak at 140.0 °C that can be attributed to the decomposition process. The
same experiment for the tricyclohexane triperoxid showed that the crystal decomposed
after 120 °C.25 It should be noted that compounds 3a-i are also stable in deuterated
solvents (toluene, chloroform) for 3 months.
The study of cytotoxic properties of Ad-substituted N-Aryl-
tetraoxaspiroalkanes
The compounds 3b, 3e, 3g and 3h were evaluated for their in vitro antitumor
activity (cytotoxicity) towards 60 cell lines of nine different types of human cancers
(lung, colon, central nervous system, ovary, renal, prostate, breast tumors, leukemia, and
melanoma) according into the protocols available at the National Cancer Institute (NCI,
26-31
Bethesda, USA)
in a single concentration 10-5. Each cell line was inoculated and
preincubated on a microtiter plate, after that the test compound was added and the culture
was incubated for 48 h. Results were reported as the percent of growth of the treated cells
compared to the untreated control cells. According to the NCI criteria (reduction of the
growth of any cancer cell lines to ca. 32% or less), compounds 3e and 3h were found to
be inactive for the NCI criteria. The compounds 3b and 3g which inhibited the cells
growth or killed cells of some cell lines were identified as «active». The compound 3b
was active towards renal cancer cells UO-31 (20.69%) and melanoma cells LOX IMVI (-
61.56%), the compound 3g was active towards leukemia cells K-562 (26.74%) and SR (-
19.22%), non-small cell lung cancer cells HOP-92 (29.03%), melanoma cells LOX IMVI
(-82.16%), ovarian cancer cells IGROV1 (16.50%), renal cancer cells 786-0 (12.59%),
CAKI-1 (25.99%) and UO-31 (-74.86%).
It seems that the compounds 3b and 3g may be promising as the potential
anticancer substances for more detailed in vitro studies.
Conclusions
New 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)} were
prepared by the ring transformation reaction of spiro{adamantane-[2,3’]-
(1′,2′,4′,5′,7′-pentaoxacane)} with arylamines catalyzed by Sm(NO3)3·6H2O. The
product structures incorporate the spiro-Ad and nitrogen-containing peroxide -N-
CH2-O-O moieties, which are responsible for high antimalarial activity.

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In
the
crystals of 7′-R-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-
tetraoxazocanes)}, where R = p-FC6H4, p-ClC6H4, p-CH3OC6H4, o-CH3OC6H4,
which were studied by X-ray diffraction, the tetraoxazocane ring occurs in the twist-
chair conformation with axial N-aryl substituents. The О–О bond lengths in the
tetraoxazocane moiety were found to be non-equivalent.
A multicomponent equilibrium between conformations with different spatial
arrangements of the ring was found to exist in solution; at room temperature. The
chair-chair conformer was separately identified, whereas the twist-chair and chair-
boat conformers form an equilibrium mixture. Criteria for NMR signal assignment
for 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} systems were
proposed.
The thermal stability of 7′-(4-methoxyphenyl)spiro{adamantane-[2,3′]-
(1′,2′,4′,5′,7′-tetraoxazocane)} was revealed by DSC experiment. The Ad-
substituted N-aryl-tetraoxazaspiroalkanes were found to be thermally stable up to
100°C.
The compounds 7′-(4-fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-
tetraoxazocane)} 3b and 7′-(2-methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-
tetraoxazocane)} 3g showed cytotoxicity towards melanoma cells LOX IMVI (3b, -
61.56%; 3g, -82.16%), leukemia cells SR (3g, -19.22%) and renal cancer cells UO-
31 (3g, -74.86%).
Experimental Section
General experimental methods
All reactions were performed at room temperature in air in a round-bottom flask
1
13
equipped with a magnetic stir bar. The H and C NMR spectra were recorded on a
Bruker Avance-400 spectrometer (400 and 100 MHz, respectively) in Tol-d6 and CDCl3
with TMS as the internal standard. Two-dimensional homonuclear (COSY, NOESY) and
1
heteronuclear (1H-13C HSQC, H-13C HMBC) NMR experiments were carried out by
Bruker standard procedures at the same operating frequencies. The mixing time for the
NOESY experiments was 0.3 sec. The constants and activation parameters of
intermediate exchange were found using line shape analysis of NMR spectra with the
program Bruker TopSpin 3.0. Atmospheric pressure chemical ionization (APCI) mass

15
ACCEPTED MANUSCRIPT
spectra of the compounds 3b,c,e-h and 5 were obtained on a HPLC mass-spectrometer
LCMS-2010EV (Shimadzu) in positive ions mode at the ionizing electrode potential of
4.5 kV. The temperature of the APCI interface was 250 °C, the heater’s and the
desolvation line’s temperature was 200 and 230 °C, respectively. The nebulizer gas
(nitrogen) flow rate was 1.5 L min−1. The high-frequency lenses (Q-array) voltage was
5V. Samples solutions (direct syringe sample inlet) were in acetonitrile, the mobile phase
(acetonitrile/water (83:17)) flow rate was 0.1 mL min−1. The progress of reactions was
monitored by TLC on Sorbfil (PTSKh-AF-V) plates, with a 5:1 hexane: EtOAc mixture
as the eluent (compounds 3a-i) and visualization with I2 vapor. For column
chromatography, silica gel KSK (100-200 ꢀm) was used.
All calculations were carried out using a program Gaussian 09.32 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 functional33 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 confirmed through the
calculation of the force constant (Hessian) matrix and the analysis of the resulting
frequencies. All minima were verified to have no negative frequencies. NMR shifts were
calculated using the method GIAO34, which is implemented in the Gaussian 09 program.
Visualization of quantum chemical data was carried out with the programs ChemCraft.35
The X-ray diffraction data were collected on a Xcalibur Gemini Еos diffractometer
equipped with a EOS CCD detector and a monochromatized source of MoKα radiation
(graphite monochromator, MoKα radiation, λ = 0.71073 Å, ω-scan mode, 2θmax = 62°).
The data were collected and processed using the CrysAlisPro Oxford Diffraction Ltd.
program.36 The structures were solved by direct methods and refined by full-matrix least-
squares in the anisotropic approximation for non-hydrogen atoms. All the hydrogen
atoms were placed in the idealized locations and refined as riding model. The
calculations were carried out by the SHELX program package.37
DSC Measurements. The measurement were carried out with a NETZSCH DSC
204F1 instrument (Phoenix 240-12-0332) under a flow of nitrogen (50 mL/min). The
sample was placed in a standard sealed aluminum pan. The following temperature

16
ACCEPTED MANUSCRIPT
program was used: isothermal for 1 min, ramp down to 50 °C at a heating rate of 5
°C/min. The data were recorded and analyzed on a TA program.
Anticancer activity in vitro. The method for testing the in vitro antitumor activity
of compounds in National Cancer Institute, USA is described26-31 in and at the site
www.dtp.nci.nih.gov.
Ring
transformation
reaction
of
pentaoxaspirocycloalkanes
with
aryl(hetaryl)amines catalyzed by Sm(NO3)3·6H2O. General procedure. A Schlenk
vessel mounted on a magnetic stirrer under argon was charged with THF (5 mL),
Sm(NO3)3·6H2O (0.5 mol), primary amine (10 mmol), and spiro{adamantane-[2,3’]-
(1′,2′,4′,5′,7′-pentaoxacane)} (11 mmol). The reaction mixture was stirred at room
о
temperature (~20 С) for 6 h, the solvent was evaporated, and the residue was
chromatographed on a SiO2 column to give pure heterocycles, 7′-arylspiro{adamantane-
[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)} 3a-i.
7′-(2-Fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3a)
1
Pale yellow oil (84% yield). Сonformers B+C H-NMR (400 MHz, DMSO-d6, 25
oC); δ 1.60-1.65 (m, 2Н, СH2-Ad), 1.78-1.79 (m, 4Н, СH2-Ad), 1.87-1.91 (m, 4Н, CH2-
Ad), 1.94-1.96 (m, 4Н, CH2-Ad), 2.16 (br.s, 2Н, СН-Ad), 5.26 (d, 2Н, J = 10.0 Hz,
OСН N), 5.30 (d, 2Н, J = 10.0 Hz, OСН N),
7.14-7.17 (m, 1Н, СН-Ar), 7.17-7.27 (m,
2
2
conformer A: 1.60-1.65 (m, 2Н, CH -Ad), 1.75
2Н, СН-Ar), 7.43-7.47 (m, 1Н, СН-Ar),
2
(br.s, 1Н, НС-Ad), 1.78-1.79 (m, 4Н, CH2-Ad), 1.87-1.91 (m, 4Н, CH2-Ad), 1.94-1.96
(m, 4Н, CH2-Ad), 2.60 (br.s, 1Н, НС-Ad), 5.42 (d, 2Н, J = 10.0 Hz, OСН2N), 5.48 (d,
2Н, J = 10.0, OСН N), 7
.09-7.12 (m, 1Н, НС-Ar), 7.14-7.17 (m, 1Н, НС-), 7.17-7.27 (m,
2
13
o
; conformers B+C, C (100 MHz, DMSO-d , 25 C),: δ 26.84, 31.96, 33.61,
2Н, НС)
6
34.05, 36.97, 87.76, 110.49, 116.47, 116.63 (J = 16.0 Hz), 124.48, 124.55 (J = 7.0 Hz),
125.36, 135.58, 156.24, 154.30 (J = 194.0 Hz), conformer A: 26.90, 30.69, 32.90, 33.97,
34.37, 37.05, 89.99, 110.49, 116.90, 117.07 (J = 17.0 Hz), 125.03, 124.90 (J = 13.0 Hz),
125.63, 135.48, 156.24, 154.30 (J = 194.0 C).
7′-(4-Fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3b)

17
ACCEPTED MANUSCRIPT
1
Colorless crystal (98% yield); mp 109-110oC. Conformers B+C H-NMR (400
o
MHz, CDCl3, 25 C): δ 1.67-1.69 (m, 2Н, СН2-Ad), 1.85-1.90 (m, 8Н, СН2-Ad), 2.07-
2.10 (m, 4Н, CH2-Ad), 2.23 (br.s, 2Н, CH2-Ad), 5.29 (d, 2Н, J = 10.0 Hz, OСН2N), 5.37
(d, 2Н, J = 10.0 Hz, OСН N),
6.98-7.00 (m, 2Н, СН-Ar), 7.09-7.12 (m, 2Н, СН-Ar),
2
conformer A: 1.67-1.69 (m, 2Н, СН2), 1.77 (br.s, 1Н, СН), 1.85-1.90 (m, 4Н, СН2), 1.99-
2.03 (m, 4Н, CH2), 2.07-2.10 (m, 4Н, CH2), 2.80 (br.s, 1Н, СН), 5.43 (d, 2Н, J = 10.0
Hz, OСН N), 5.55 (d, 2Н, J = 10.0 Hz, OСН N), 6
.98-7.00 (m, 1Н, СН), 7.05-7.06 (m,
2
2
13
o
; conformers B+C C-NMR (100 MHz, CDCl , 25 C): δ 27.04, 31.95,
1Н, СН-Ar)
3
33.70, 34.23, 37.22, 86.73, 111.04, 115.51, 115.69 (J = 18.0 Hz), 119.82, 119.88 (J = 6.0
Hz), 143.39, 157.34, 159.35 (J = 191.0 Hz), conformer A: 27.08, 30.78, 33.02, 34.10,
34.6, 37.32, 89.34, 113.36, 115.81, 115.98 (J = 17.0 Hz), 121.36, 121.29 (J = 7.0 Hz),
143.39, 159.73, 157.77 (J = 196.0 Hz). APCI MS (m/z (%)): 124 (19%) [C7H6FN+H]+;
165 (38%) [C7H6FN+H+CH3CN]+; 167 (55%) [C10H14O2+H]+; 183 (44%)
[C10H14O3+H]+;
[C10H14O2+H+CH3CN]+.
192
(24%)
[C10H14O+H+CH3CN]+;
208
(100%)
7′-(3-Chlorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3c)
1
Yellow crystal (90% yield); mp 78-80oC. Conformers B+C H-NMR (400 MHz,
CDCl3, 25 oC): δ 1.63-1.68 (m, 6Н, СН2-Ad), 1.88-1.85 (m, 4Н, CH2-Ad), 2.06-2.09 (m,
4Н, CH2-Ad), 2.20 (br.s, 2Н, СН-Ad), 5.33 (d, 2Н, J = 10.0 Hz, OСН2N), 5.39 (d, 2Н, J
= 10.0 Hz, OСН N),
6.96-6.99 (m, 2Н, СН-Ar), 7.10-7.11 (m, 1Н, СН-Ar), 7.20-7.24 (m,
2
conformer A: 1.63-1.68 (m, 2Н, СН -Ad), 1.76 (br.s, 1Н, СН-Ad), 1.85-
1Н, СН-Ar),
2
1.88 (m, 4Н, СН2-Ad), 2.01-2.02 (m, 4Н, CH2-Ad), 2.06-2.09 (m, 4Н, CH2-Ad), 2.70
(br.s, 1Н, СН-Ad), 5.42 (d, 2Н, J = 10.0 Hz, OСН2N), 5.63 (d, 2Н, J = 10.0 Hz,
OСН N), 6
.96-6.99 (m, 1Н, СН-Ar), 7.05-7.06 (m, 1Н, СН-Ar), 7.10-7.11 (m, 1Н, СН-
; conformers B+C 13C-NMR (100 MHz, CDCl , 25 oC): δ
2
Ar), 7.20-7.24 (m, 1Н, НС-Ar)
3
27.02, 31.93, 33.67, 34.25, 37.21, 85.72 (OCH2N), 111.17, 115.5, 117.60, 121.60,
130.10, 134.81, 148.09, conformer A: 27.02, 30.73, 32.97, 34.09, 34.63, 37.29, 88.34,
113.60, 116.79, 118.95, 122.43, 130.35, 134.99, 147.69. APCI MS (m/z (%)):140 (100%)
[C7H6ClN+H]+; 167 (44%) [C10H14O2+H]+; 181 (28%) [C7H6ClN+H+CH3CN]+; 208
(39%) [C10H14O2+H+CH3CN]+.

18
ACCEPTED MANUSCRIPT
7′-(4-Chlorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3d)
1
Colorless crystal (88% yield); mp 138-140oC. Conformers B+C H-NMR (400
o
MHz, CDCl3, 25 C): δ 1.65-1.68 (m, 6Н, СН2-Ad), 1.85-1.90 (m, 4Н, СН2-Ad), 2.05-
2.08 (m, 4Н, CH2-Ad), 2.20 (br.s, 2Н, СН-Ad), 5.32 (d, 2Н, J = 10.0 Hz, OСН2N), 5.39
(d, 2Н, J = 10.0 Hz, OСН N),
7.00-7.06 (m, 2Н, СН-Ar), 7.25-7.27 (m, 2Н, СН-Ar),
2
conformer A: 1.65-1.68 (m, 6Н, СН2), 1.76 (br.s, 1Н, СН), 1.84-1.85 (m, 4Н, СН2), 2.05-
2.08 (m, 4Н, CH2), 2.69 (br.s, 1Н, СН), 5.42 (d, 2Н, J = 10.0 Hz, OСН2N), 5.61 (d, 2Н, J
= 10.0 Hz, OСН N),
conformers B+C
7.00-7.06 (m, 2Н, СН), 7.25-7.27 (m, 2Н, СН);
2
o
13C-NMR (100 MHz, CDCl3, 25 C): δ 27.02, 31.92, 33.68, 34.24, 37.20, 86.04, 111.13,
118.91, 129.05, 126.76, 145.58, conformer A: 27.02, 30.73, 32.99, 34.09, 34.62, 37.29,
88.64, 111.13, 120.28, 129.32, 126.76, 145.58.
7′-(2-Methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3e)
Light brown oil (87% yield). Conformers B+C 1H-NMR (400 MHz, CDCl3, 25 oC):
δ 1.70-1.76 (m, 6Н, СН2-Ad), 1.93-1.94 (m, 4Н, СН2-Ad), 2.03-2.14 (m, 4Н, CH2-Ad),
2.30 (s, 3Н, СН3), 2.43 (br.s, 2Н, СН), 5.19 (d, 2Н, J = 10.0 Hz, OСН2N), 5.23 (d, 2Н, J
= 10.0 Hz, OСН N),
7.12-7.16 (m, 1Н, СН-Ar), 7.22-7.26 (m, 2Н, СН-Ar), 7.78-7.80 (m,
2
conformer А: 1.70-1.76 (m, 2Н, СН2-Ad), 1.93-1.94 (m, 4Н, CH -Ad),1.98
1Н, СН-Ar),
2
(br.s, 1Н, СН-Ad), 2.12-2.14 (m, 4Н, CH2-Ad), 2.17-2.21 (m, 4Н, CH2-Ad), 2.27 (s, 3Н,
СН3), 3.13 (br.s, 1Н, СН-Ad), 5.26 (d, 2Н, J = 10.0 Hz, OСН2N), 5.53 (d, 2Н, J = 10.0
Hz, OСН N),
7.12-7.16 (m, 1Н, СН-Ar), 7.22-7.26 (m, 2Н, СН-Ar),7.78-7.80 (m, 1Н,
2
13
o
conformers B+C C-NMR (100 MHz, CDCl , 25 C): δ 18.63 (СН ), 27.15,
СН-Ar);
3
3
32.28, 33.80, 34.54, 37.33, 88.44, 110.89, 125.48, 126.73, 126.82, 130.86, 133.04,
146.49, conformer А: 18.41, 27.22, 31.12, 33.16, 34.23, 36.33, 37.43, 90.52, 112.68,
125.68, 126.43, 126.91, 131.15, 132.67, 144.10. APCI MS (m/z (%)):120 (32%)
[C8H9N+H]+; 136 (7%) [C8H9NO+H]+; 161 (35%) [C8H9N+H+CH3CN]+; 167 (25%)
[C10H14O2+H]+; 177 (50%) [C8H9NO+H+CH3CN]+; 183 (100%) [C10H14O3+H]+; 208
(57%) [C10H14O2+H+CH3CN]+; 224 (21%) [C10H14O3+H+CH3CN]+.
7′-(3-Methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3f)

19
ACCEPTED MANUSCRIPT
Yellow crystal (93% yield); mp 64-66oC. Conformers B+C H-NMR (400 MHz,
CDCl3, 25 oC): δ 1.63-1.72 (m, 4Н, СН2-Ad), 1.69-1.72 (m, 2Н, СН2-Ad), 2.04-2.07 (m,
4Н, CH2-Ad), 2.12-2.15 (m, 4Н, CH2-Ad), 2.39 (s, 3Н, СН3), 2.77 (br.s, 2Н, СН-Ad),
1
5.36 (d, 2Н, J = 12.0 Hz, OСН N), 5.44 (d, 2Н, J = 12.0 Hz, OН СN),
6.84-6.86 (m, 2Н,
2
2
conformer А: 1.63-1.72 (m, 4Н,
СН), 6.97-6.99 (m, 1Н, СН), 7.20-7.24 (m, 1Н, СН),
СН2-Ad), 1.69-1.72 (m, 2Н, СН2-Ad), 1.81 (br.s, 1Н, СН-Ad), 2.04-2.07 (m, 4Н, CH2-
Ad), 2.12-2.15 (m, 4Н, CH2-Ad), 2.39 (s, 3Н, СН3), 2.75 (br.s, 1Н, СН-Ad), 5.44 (d, 2Н,
J = 12.0 Hz, OСН N), 5.69 (d, 2Н, J = 12.0 Hz, OСН N),
6.88-6.90 (m, 1Н, СН-Ar),
2
2
conformers B+C 13C-NMR (100
6.90-6.93 (m, 2Н, СН-Ar), 7.20-7.24 (m, 1Н, СН-Ar);
o
MHz, CDCl3, 25 C): δ 21.78, 27.11, 31.96, 33.74, 34.30, 37.30, 86.20, 110.97, 114.84
(CH), 118.40, 122.56, 128.97, 138.82, 146.98, conformer А: 21.78, 27.50, 29.75, 33.06,
34.15, 34.67, 37.39, 88.84, 113.44, 116.15, 119.77, 123.31, 129.18, 139.12, 146.57.
APCI MS (m/z (%)):120 (11%) [C8H9N+H]+; 136 (13%) [C8H9NO+H]+; 161 (21%)
[C8H9N+H+CH3CN]+; 167 (41%) [C10H14O2+H]+; 177 (100%) [C8H9NO+H+CH3CN]+;
208 (75%) [C10H14O2+H+CH3CN]+; 191 (19%) [C9H11NO+H+CH3CN]+; 192 (16%)
[C10H14O+H+CH3CN]+.
7′-(4-Methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3g)
1
Yellow crystal (80% yield); mp 107-108oC. Conformers B+C H-NMR (400
o
MHz, CDCl3, 25 C): δ 1.68-1.70 (m, 2Н, СН2-Ad), 1.85-1.91 (m, 4Н, СН2-Ad), 2.00-
2.02 (m, 4Н, CH2-Ad), 2.02-2.05 (m, 4Н, CH2-Ad), 2.25-2.26 (m, 2Н, СН-Ad), 2.33 (s,
3Н, СН ), 5.33 (d, 2Н, J = 8.0 Hz, OСН N), 5.41 (d, 2Н, J = 8.0 Hz, OСН N),
6.04-7.06
3
2
2
conformer А: 1.68-1.70 (m, 2Н, СН -Ad),
(m, 2Н, СН-Ar), 7.11-7.13 (m, 2Н, СН-Ar),
2
1.78 (br.s, 1Н, СН-Ad), 2.00-2.02 (m, 8Н, CH2-Ad), 2.09-2.13 (m, 4Н, CH2-Ad), 2.33 (s,
3Н, СН3), 2.81 (br.s, 1Н, СН-Ad), 5.43 (d, 2Н, J = 8.0 Hz, OН2СN), 5.63 (d, 2Н, J = 8.0
Hz, OСН N),
conformers B+C 13C-NMR
6.99-6.97 (m, 2Н, СН), 7.11-7.13 (m, 2Н, СН);
2
o
(100 MHz, CDCl3, 25 C): δ 20.56, 27.08, 31.94, 33.74, 34.27, 37.28, 86.50, 110.94,
118.00, 129.60, 131.14, 144.68, conformer А: 20.56, 27.47, 30.70, 34.13, 34.63, 37.38,
37.39, 89.12, 113.34, 119.39, 129.88, 132.03, 146.28.
7′-(2-Methoxyphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3h)

20
ACCEPTED MANUSCRIPT
1
Colorless crystal, (93% yield); mp 89-90oC. Conformers B+C H-NMR (400
o
MHz, CDCl3, 25 C): δ 1.69-1.71 (m, 2Н, СН2-Ad), 1.87-1.88 (m, 4Н, СН2-Ad), 2.03-
2.06 (m, 4Н, CH2-Ad), 2.11-2.14 (m, 4Н, CH2-Ad), 2.32 (br.s, 2Н, СН-Ad), 3.86 (s, 3Н,
ОСН ), 5.28 (d, 2Н, J = 10.0 Hz, OСН N), 5.35 (d, 2Н, J = 10.0 Hz, OСН N),
6.89-6.91
3
2
2
conformer А:
(m, 1Н, СН-Ar), 6.94-6.98 (m, 1Н, СН-Ar), 7.11-7.17 (m, 2Н, СН-Ar),
1.69-1.71 (m, 2Н, СН2-Ad), 1.79 (br.s, 1Н, СН-Ad), 1.87-1.88 (m, 2Н, СН2-Ad), 2.03-
2.06 (m, 4Н, CH2-Ad), 2.11-2.14 (m, 4Н, CH2-Ad), 2.98 (br.s, 1Н, СН-Ad), 3.86 (s, 3Н,
ОСН ), 5.46 (d, 2Н, J = 12.0 Hz, OСН N), 5.52 (d, 2Н, J = 12.0 Hz, OСН N),
6.89-6.91
3
2
2
conformers B+C
(m, 1Н, СН-Ar), 6.94-6.98 (m, 1Н, СН-Ar), 7.61-7.63 (m, 2Н, СН-Ar);
o
13C-NMR (100 MHz, CDCl3, 25 C): δ 27.10, 32.16, 33.76, 34.22, 37.30, 55.40, 88.33,
110.84, 111.22, 121.13, 125.07, 136.34, 152.53, conformer А: 27.15, 30.91, 33.13, 34.18,
34.53, 37.39, 55.40, 90.24, 110.84, 111.39, 121.20, 124.69, 125.46, 135.9, 152.53. APCI
MS (m/z (%)): 136 (86%) [C8H9NO+H]+; 150 (22%) [C9H11NO+H]+; 152 (44%)
[C8H9NO2+H]+; 167 (34%) [C10H14O2+H]+; 177 (50%) [C8H9NO+H+CH3CN]+; 183
(83%) [C10H14O3+H]+; 193 (100%) [C8H9NO2+H+CH3CN]+; 198 (26%) [C9H11NO4+H]+;
208 (53%) [C10H14O2+H+CH3CN]+; 224 (9%) [C10H14O3+H+CH3CN]+; 239 (22%)
[C9H11NO4+H+CH3CN]+.
7′-(4-Methoxyphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} (3i)
1
o
Brown oil, (89% yield). Conformers B+C H-NMR (400 MHz, CDCl3, 25 C): δ
1.68-1.69 (m, 2Н, СН2-Ad), 1.84-1.85 (m, 4Н, СН2-Ad), 2.00-2.03 (m, 4Н, CH2-Ad),
2.09-2.12 (m, 4Н, CH2-Ad), 2.25 (br.s, 2Н, СН-Ad), 3.79 (s, 3Н, ОСН3), 5.27 (d, 2Н, J =
10.0 Hz, OСН N), 5.35 (d, 2Н, J = 10.0 Hz, OСН N),
6.85 (d, 2Н, J = 10.0 Hz, СН-Ar),
2
2
conformer А: 1.68-1.69 (m, 2Н, СН -Ad), 1.76 (br.s,
7.12 (d, 2Н, J = 8.0 Hz, СН-Ar),
2
1Н, СН), 1.84-1.85(m, 2Н, СН2-Ad), 2.00-2.03 (m, 4Н, CH2-Ad), 2.09-2.12 (m, 4Н,
CH2-Ad), 2.84 (br.s, 1Н, СН-Ad), 3.90 (s, 3Н, ОСН3), 5.42 (d, 2Н, J = 10.0 Hz,
OСН N), 5.52 (d, 2Н, J = 10.0 Hz, OСН N),
6.85 (d, 2Н, J = 10.0 Hz, СН-Ar), 7.01-7.07
2
2
13
o
conformers B+C C-NMR (100 MHz, CDCl , 25 C): δ 27.06, 31.96,
(m, 2Н, СН-Ar);
3
33.73, 34.24, 37.27, 55.50, 87.19, 110.91, 114.32, 120.39, 140.90, 155.03, conformer А:
27.10, 30.76, 33.07, 34.13, 34.61, 37.27, 55.50, 89.76, 114.16, 114.50, 121.66 , 140.01,
155.90.

21
ACCEPTED MANUSCRIPT
4-Spiro[adamantane-2,3’-[1,2,4,5,7] tetraoxazocane]-7’-yl)aniline (5)
1
o
White solid (84% yield), mp 106-108oC. H-NMR (400 MHz, CDCl3, 25 C): δ
1.69-1.72 (m, 2Н, СН2-Ad), 1.89-1.90 (m, 4Н, СН2-Ad), 2.03-2.05 (m, 8Н, CH2-Ad),
2.35 (br.s, 2Н, СН-Ad), 10.42 (br.s, 2Н, NН ), 5.24 (d, 4Н, J = 10.0 Hz, OСН N),
6.95-
2
2
6.98 (m, 1Н, СН), 7.03-7.05 (m, 1Н, СН), 7.53-7.57 (m, 1Н, СН), 7.95-7.96 (m, 1Н,
o
13
(100 MHz, CDCl , 25 C): δ 27.08, 31.49, 33.69, 37.16, 91.74, 111.30,
СН); C-NMR
3
117.83, 119.59, 130.94, 136.95, 162.19, 174.70. APCI MS (m/z (%)): 151 (24%)
[C8H10N2O+H]+; 167 (100%) [C8H10N2O2+H]+; 192 (92%) [C8H10N2O+H+CH3CN]+; 208
(97%) [C8H10N2O2+H+CH3CN]+.
2Н,5Н-1,6-(methanedioxymethano)benzo[e][1,2,4,7]dioxazocine (7)
1
o
Colorless crystal, (60% yield). H-NMR (400 MHz, DMSO-d6, 25 C): δ 5.08 (d,
13
4Н, J = 8.0 Hz, CH2), 7.31-7.33 (m, 2Н,СН), 7.38-7.40 (m, 2Н,СН); C-NMR (100
MHz, CDCl3, 25 oC): δ 90.79, 129.39, 130.00.
1,3,5-Tri-aryl-1,3,5-triazinanes (10a-i). The spectral properties (1H NMR, 13C
NMR) were in good agreement with those reported in the literature.38
((2-Hydroperoxyadamantan-2-yl)peroxy)methanol (11)
1
Colorless crystal, (60% yield), mp 115-116oC. H-NMR (400 MHz, CDCl3, 25
oC): δ 1.67-1.68 (m, 2Н, СН2), 1.88-2.12 (m, 10Н, СН2), 2.33 (br.s, 2Н, СН), 5.21 (s, 2Н,
13
o
OСН2О), 9.96 (br.s, 1Н, OОН); C-NMR (100 MHz, CDCl3, 25 C): δ 27.43, 31.49,
33.73, 36.29, 37.19, 91.75, 110.11.
The crystal of compound 3b (C18H22FNO4, M = 335.37 g/mol) is orthorhombic,
space group Pna21 (No. 33); unit cell parameters: a = 12.6307(10) Å, b = 6.6410(5) Å, c
= 19.1592(14) Å, V = 1607.1(2) Å3; Z = 4, T = 293 K, ꢀ(Mo Kα) = 0.105 mm-1, Dcalc.
=
1.386 g/cm3. Altogether 10042 reflections were collected (4.252° ≤ 2Θ ≤ 58.414°)
including 3765 unique reflections (Rint = 0.0277). The final R-factors were R1 = 0.0399

22
ACCEPTED MANUSCRIPT
for the unique observed reflections with I > 2σ(I)) and wR2 = 0.0879 for all unique
reflections, ССDC № 1531630.
The crystal of compound 3d (C18H22ClNO4, M = 351.82 g/mol) is monoclinic,
space group P21/c (No. 14); unit cell parameters: a = 20.184(4)Å, b = 6.6789(7) Å, c =
12.7848(16)Å, β= 104.567(16)°, V = 1668.1(4) Å3; Z= 4, T= 293 K, ꢀ(Mo Kα) = 0.251
mm-1, Dcalc. = 1.401 g/cm3. Altogether 7580 reflections were collected (6.256o ≤ 2Θ ≤
58.288°), including 3891 unique reflections (Rint = 0.0543). The final R-factors were R1 =
0.0916 for the unique observed reflections with I > 2σ(I)) and wR2 = 0.2488 for all
unique reflections, CCDC № 1573317.
The crystal of compound 3g (C19H25NO4, M = 331.40 g/mol) is monoclinic, space
group P21/c (No. 14); unit cell parameters: a = 20.1904(17)Å, b = 6.6711(4) Å, c =
12.9057(9)Å, β = 106.432(8)°, V = 1667.3(2) Å3; Z = 4, T = 293 K, ꢀ(Mo Kα) = 0.092
mm-1, Dcalc. = 1.320 g/cm3. Altogether 7390 reflections were collected (6.312o ≤ 2Θ ≤
58.222°), including 3809 unique reflections (Rint = 0.0312). The final R-factors were R1 =
0.0972 for the unique observed reflections with I > 2σ(I)) and wR2 = 0.2638 for all
unique reflections, CCDC № 1531629.
The crystal of compound 3h (C19H25NO5, M = 347.40 g/mol) is monoclinic, space
group P21/c (No 14); unit cell parameters: a = 12.4037(10)Å, b = 14.5530(17) Å, c =
9.9903(8)Å, β = 103.023(8)°, V = 1757.0(3) Å3; Z = 4, T = 293 K, ꢀ(Mo Kα) = 0.095
mm-1, Dcalc. = 1.313 g/cm3. Altogether 8787 reflections were collected (3.37° ≤ 2Θ ≤
58.6°), including 4041 unique reflections (Rint = 0.0413). The final R-factors were R1 =
0.076 for the unique observed reflections with I > 2σ(I)) and wR2 = 0.1906 for all unique
reflections, CCDC № 1531631.
The crystal of compound 7 (C10H12N2O4, M = 224.06 g/mol) is orthorhombic,
space group Pbca (No 61); unit cell parameters: a = 7.6502(4) Å, b = 11.0598(7) Å, c =
24.2489(13) Å, V = 2051.7(2) Å3; Z = 8, T = 293 K, ꢀ(Mo Kα) = 0.114 mm-1, Dcalc.
=
1.454 g/cm3. Altogether 5263 reflections were collected (6.298° ≤ 2Θ ≤ 58.494°),
including 2401 unique reflections (Rint = 0.0372). The final R-factors were R1 = 0.0793
for the unique observed reflections with I > 2σ(I)) and wR2 = 0.2094 for all unique
reflections, CCDC № 1575317.
The crystal of compound 11 (C11H18NO5, M = 230.25 g/mol) is monoclinic, space
group P21/n (No 14); unit cell parameters: a = 8.2521(12)Å, b = 7.2813(12) Å, c =

23
ACCEPTED MANUSCRIPT
18.449(3)Å, β = 96.573(14)°, V = 1101.2(3) Å3; Z = 4, T = 293 K, ꢀ(Mo Kα) = 0.109
mm-1, Dcalc. = 1.389 g/cm3. Altogether 4928 reflections were collected (4.444° ≤ 2Θ ≤
58.262°), including 3227 unique reflections (Rint= 0.0372). The final R-factors were R1 =
0.0560 for the unique observed reflections with I > 2σ(I)) and wR2 = 0.1863 for all
unique reflections, CCDC № 1575315.
Crystallographic data for the structures in this paper were deposited with the
Cambridge Crystallographic Data Center. CCDC 1531630, 1573317, 1531629, 1531631,
1575317, 1575315 contain the supplementary crystallographic data for, respectively 3b,
3d, 3g, 3h, 7 and 11, Copies of the data can be obtained, free of charge, on application to
the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgements
This work was supported by Russian Foundation for Basic Research (RFBR
projects 16-29-10687 оfi_м). The structural studies of the compounds were performed
with unique equipment in "Agidel" collective usage centre. APCI mass spectra of the
compounds were recorded on equipment installed in the Center for Collective use
"Khimiya" (Chemistry) at Ufa Institute of Chemistry of the Russian Academy of
Sciences.
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