One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-hexaazaperhydropyrenes

Article abstract of DOI:10.1016/j.tet.2017.10.048

Catalytic methods for the synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-hexaazaperhydropyrenes have been developed. The structure was established on the basis of ¹H and ¹³C NMR spectra, 2D NMR (HSQC, HMBC, COSY, NOESY) techniques, MALDI TOF/TOF spectra, and X-ray diffraction data. Primary screening of the synthesized hexaazaperhydropyrenes for antimicrobial activity was performed.

Full text of DOI:10.1016/j.tet.2017.10.048

Tetrahedron xxx (2017) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-
2,3a,5a,7,8a,10a-hexaazaperhydropyrenes
*
Elena B. Rakhimova , Victor Yu. Kirsanov, Ekaterina S. Meshcheryakova,
Leonard M. Khalilov, Boris I. Kutepov, Askhat G. Ibragimov, Usein M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, 450075 Ufa, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2017
Received in revised form
Catalytic methods for the synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-hex-
1
13
aazaperhydropyrenes have been developed. The structure was established on the basis of H and
C
NMR spectra, 2D NMR (HSQC, HMBC, COSY, NOESY) techniques, MALDI TOF/TOF spectra, and X-ray
diffraction data. Primary screening of the synthesized hexaazaperhydropyrenes for antimicrobial activity
was performed.
29 September 2017
Accepted 17 October 2017
Available online xxx
©
2017 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Heterocyclization
Azapolycycles
Hexaazaperhydropyrenes
1
. Introduction
previously undescribed and promising for practical application, we
have studied the possibility of the one-pot preparation of 2,7-bis-
substituted hexaazaperhydropyrenes that bear methyl substituents
directly attached to a polycyclic skeleton. Preliminary experiments
have shown that the uncatalyzed interaction between the in situ
Interest in the synthesis of annelated azapolycycles is generated
by the possibility of their use as candidate compounds for the
development of drugs with analgesic, antibacterial and anti-
tumor3 properties. The annelated azapolycycles include aza-
perhydropyrenes the synthesis of which was previously performed
1
2
,4
14
prepared N,N-bis(methoxymethyl)-N-propylamine and 2,6(7)-
15
ꢀ
dimethyl-1,4,5,8-tetraazadecalins (1) and (2) at 60 C afforded the
corresponding 2,7-dipropyl-4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
5
by the reaction of 1,4,5,8-tetraazadecalin with methyl acrylate, or
by the three-component cyclocondensation of primary amines
hexaazaperhyd-ropyrenes (3) and (4) at a ratio of 1:1 in a total yield
of no more than 40%. In our work we used racemic starting material
(1) and (2) because it is very difficult to separate the 2,6- and 2,7-
isomers. To increase the yield of the desired heterocycles (3) and
(4), the reaction of bis(methoxymethyl)propylamine with 2,6(7)-
dimethyl-1,4,5,8-tetraazadecalins was carried out under the action
of catalysts based on transition and rare-earth metal salts which we
6
7,8
with formaldehyde and 1,4,5,8-tetraazadecalin. Recently, effec-
tive methods for the synthesis of hexaazaperhydropyrenes have
been developed by the intermolecular cyclization of N,N-bis(me-
thoxymethyl)-N-alkylamines or by recyclization of 1,3,5-
tricycloalkyl-1,3,5-triazines with 1,4,5,8-tetraazadecalin under the
action of catalysts based on salts of d- and f-block elements.
7,9,10
have used previously in similar heterocyclization reactions.
Among the catalysts tested, SmCl $6H O showed the highest
activity in this reaction. In the presence of 5 mol% of SmCl $6H O,
,6(7)-dimethyl-1,4,5,8-tetraazadecalins reacted with N,N-bis(me-
3
2
2
. Results and discussion
3
2
2
In continuation of our investigations7e13 into the catalytic syn-
thesis of different heterocycles, and also with the aim of developing
an effective method for the synthesis of azapolycycles that are
thoxymethyl)-N-propylamine to produce 2,7-dipropyl-4,9(10)-
dimethyl-2,3a,5a,7,8a,10a-hexaazaperhydro-pyrenes (3, 4) at a ra-
tio of ~1:1 in 81% total yield (Scheme 1). Similar results were ob-
tained by replacing the n-propyl residue on the nitrogen atom by an
n-Bu group. Intermolecular heterocyclization of 2,6(7)-dimethyl-
*
Corresponding author.
E-mail addresses:
E.B. Rakhimova).
1,4,5,8-tetraazadecalins with N,N-bis(methoxymethyl)-N-alkyl-
reb2604@gmail.com,
Rakhimovaelena@mail.ru
amines, prepared from linear primary alkyl amines, under
(
https://doi.org/10.1016/j.tet.2017.10.048
040-4020/© 2017 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

2
E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
Scheme 1. Intermolecular heterocyclization of N,N-bis(methoxymethyl)-N-alkylamines with 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins.
optimized reaction conditions (5 mol% SmCl
3
$6H
2
O, MeOHeH
2
O,
3
h), 1,3,5-tricycloalkyl-1,3,5-triazines reacted with 2,6(7)-
ꢀ
2
0
C, 3 h) led to the formation of 2,7-dialkyl-4,9(10)-dimethyl-
dimethyl-1,4,5,8-tetraazadecalins to selectively produce 2,7-
2
,3a,5a,7,8a,10a-hexaaza-perhydropyrenes (3, 4) and (5, 6) at a ratio
dicycloalkyl-4,9-dimethyl-2,3а,5а,7,8а,10а
pyrenes (9e14) in 79e92% yield (Scheme 2).
It should be noted that in the reaction of 1,3,5-tricyclopropyl-
1,3,5-triazine with 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins, along
hexaazaperhydro-
of ~1:1 in 81e83% total yield according to Scheme 1. Because of
their close polarity (R ), we failed to satisfactorily separate hex-
aazaperhydropyrenes (3e6) using column chromatography. In the
f
13
C NMR spectra, compounds (3, 4) and (5, 6) gave two sets of
signals corresponding to the isomeric mixture of 4,9(10)-dimethyl-
,3а,5а,7,8а,10а-hexaazaperhydropyrenes. Diastereomeric products
with
2,7-dicyclopropyl-4,9-dimethyl-2,3a,5a,7,8a,10a-hex-
aazaperhydropyrene (9) as the major isomer, we have observed the
formation of the minor 4,10-isomer. The 3:1 (75:25) ratio of iso-
mers was determined from the integration of four doublets in the
region of 2.80e3.02 ppm which correspond to protons at positions
2
13
are readily identifiable in the C NMR spectra. Thus, one signal at
2.7 ppm corresponds to carbon atoms of the symmetric 4,9-
8
8
isomer at positions C-10b and C-10c. Due to the loss of molecular
symmetry, carbon atoms of the 4,10-isomer at positions C-10b and
C-10c resonate in the form of two signals at 82.2 and 83.2 ppm.
Under the developed reaction conditions, branched amines (iso-
C-1,6 and C-3,8. The possible mechanism for the reaction between
1,3,5-tricycloalkyl-1,3,5-triazines and 2,6(7)-dimethyl-1,4,5,8-
16e18
tetraazadecalins involves
several stages, namely, coordina-
tion of the triazine tertiary nitrogen atom with the metal catalyst,
ring-opening of the triazine ring to produce an iminium ion,
nucleophilic addition of the tetraazadecalin secondary nitrogen
atom to the resulting carbocation, and subsequent cyclization with
PrNH
,3а,5а,7,8а,10а-hexaazaperhydropyrenes (7, 8) in 77e79% yield
Scheme 1), while only trace amounts of 4,10-dimethyl derivatives
2 2
, tert-BuNH ) predominantly form 2,7-dialkyl-4,9-dimethyl-
2
(
8
1
were detected in the NMR spectra.
formation of the hexaazaperhydropyrene molecule. The H NMR
spectra of compounds (9e14) contained two pairs of characteristic
doublet signals with a geminal spin-spin coupling constant equal to
12 Hz, ascribed to the methylene protons of the carbon atoms,
located between two nitrogen atoms, at positions H-1,6 and H-3,8
Based on our results and the literature data,16,17 it can be
assumed that the catalytic cycle of the reaction between 2,6(7)-
dimethyl-1,4,5,8-tetraazadecalines and N,N-bis(methoxymethyl)-
N-alkylamine includes the step of coordinating the oxygen atom
with the metal catalyst.1 Subsequent nucleophilic addition of the
nitrogen atom in tetraazadecalin to the iminium ion formed under
the reaction conditions leads to intermolecular cyclization to give
7
8
13
of the pyrene molecule. In the C NMR spectra of compounds
(9e14), there are five signals of equal intensity. Two of them, which
appear in the region of 51.3e51.6 and 56.3e56.6 ppm, belong to
carbon atoms at positions С-4,9 and С-5,10 of the dimethyl-
substituted tetracyclic skeleton. Three other signals in the region
67.7e71.1, 71.1e74.4, and 82.5e82.8 ppm correspond to carbon
atoms located between the nitrogen atoms at positions C-3,8, C-1,6
and C-10b,10c, respectively. The assignment of the signals was
carried out based on two-dimensional homo- (COSY, NOESY) and
heteronuclear (HSQC, HMBC) NMR experiments. Molecular peaks
in the positive ion mode MALDI TOF/TOF mass spectra confirm the
proposed structures.
7
hexaazaperhydropyrenes.
8
We have previously reported that 1,3,5-tricycloalkyl-1,3,5-
triazines can be used as efficient aminomethylation reagents in
the synthesis of N-substituted hexaazaperhydropyrenes. In our
subsequent experiments we investigated the possibility of the se-
lective synthesis of 2,7-dicycloalkyl-substituted 4,9-dimethyl-
2
,3a,5a,7,8a,10a-hexaazaperhydropyrenes through the catalytic re-
action of 1,3,5-tricycloalkyl-1,3,5-triazines with 2,6(7)-dimethyl-
,4,5,8-tetraazadecalins. It has been shown that under the opti-
1
ꢀ
mized reaction conditions (5 mol% NiCl
2
$6H
2
O, MeOHeH
2
O, 20 С,
Single crystals of compound (9) were obtained by slow
Scheme 2. Cyclization of 1,3,5-tricycloalkyl-1,3,5-triazines with 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins.
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
3
ꢀ
2
reaction conditions (10 wt% zeolite Y, MeOHeH O, 20 С, 3 h) to
evaporation from MeOH at room temperature. The obtained crys-
tals belong to the triclinic crystal system. According to X-ray
diffraction data (Fig. 1), the molecule of compound (9) has an
inversion centre. The trans-hexaazaperhydropyrene skeleton is
formed by two piperazine and two triazine rings, which adopt the
chair conformation. The nitrogen atoms have a pyramidal confor-
mation. The cyclopropane substituents occupy an axial position
relative to the plane of the tetracyclic core and are in a trans
configuration relative to each other.
Our further studies aimed at elucidating the possibility of the
selective synthesis of 2,7-diadamantane-substituted hex-
aazaperhydropyrenes. Attempts to produce N,N-bis(methox-
ymethyl)-N-adamantylamines or 1,3,5-triadamantyl-1,3,5-triazines
as the starting aminomethylation reagents were unsuccessful,
possibly due to the bulky adamantyl substituent. We have devel-
oped a new approach to the synthesis of previously undescribed
afford 2,7-diadamantyl-substituted 4,9-dimethyl-2,3а,5а,7,8а,10а-
hexaazaperhydropyrenes (15e19) in 50e67% yield (Scheme 3).
1
13
Resonance assignments of the H and C NMR spectra for (15e19)
were made by two-dimensional homo- (COSY, NOESY) and heter-
onuclear (HSQC, HMBC) NMR experiments. In the positive-ion
mode, MALDI-TOF/TOF MS analysis successfully confirmed the
proposed structures.
At the University of Queensland (Australia), a primary antimi-
crobial screening of the synthesized hexaazaperhydropyrenes has
been performed for antifungal and antibacterial activity. Bacterial
species like Escherichia coli, Klebsiella pneumoniae, Acinetobacter
baumannii, Pseudomonas aeruginosa, Staphylococcus aureus,
Candida albicans and Cryptococcus neoformans were used as test
cultures. The results of biological tests have shown that 2,7-
dicyclopentyl-4,9-dimethyl-2,3a,5a,7,8a,10a-hexaazaperhydro-pyr-
ane (10) is active against fungi of the genus Cryptococcus neofor-
mans var. Grubii (the inhibition value exceeds 80%) and is partially
active against bacteria of the genus Staphylococcus aureus (the in-
hibition value ranges from 50.9% to 79.9%).
2
,7-diadamantyl-substituted
4,9-dimethyl-2,3а,5а,7,8а,10а-hex-
aazaperhydropyrenes through the one-pot catalytic condensation
reaction between adamantylamines, formaldehyde, and 2,6(7)-
dimethyl-1,4,5,8-tetraazadecalins. Among the catalysts tested in
19
this reaction, the high-phase purity granular zeolite Y in H form
having a high crystallinity degree showed the greatest activity. We
have found that one-pot multicomponent condensation between
3. Conclusions
adamantylamines
(adamantyl-1-amine,
adamantyl-2-amine,
Thus, we have developed a new one-pot catalytic method for the
rimantadine, 3,5-dimethyladamantyl-1-amine, 1-hydroxy-ada-
mantyl-3-amine), formaldehyde, and 2,6(7)-dimethyl-1,4,5,8-
tetraazadecalins (1, 2) occurs selectively under the developed
synthesis of promising 2,7-bis-substituted 4,9(10)-dimethyl-
,3а,5а,7,8а,10а-hexaazaperhydropyrenes. These approaches
2
include intermolecular heterocyclization of N,N-bis(methox-
ymethyl)-N-alkylamines, cyclization of 1,3,5-tricycloalkyl-1,3,5-
triazines with 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins under the
action of catalysts based on salts of d- and f-block elements, and
also the zeolite-catalyzed multicomponent condensation between
adamantylamines, formaldehyde, and 2,6(7)-dimethyl-1,4,5,8-
tetraazadecalins.
4. Experimental section
The NMR spectra, including two-dimensional homo- (COSY,
NOESY) and heteronuclear (HSQC, HMBC) spectra, were recorded
1
on a Bruker Avance 500 spectrometer at 500.17 MHz for H and
13
1
25.78 MHz for C according to standard Bruker procedures. CDCl
3
was used as the solvent, and tetramethylsilane, as the internal
standard. The MALDI TOF/TOF mass spectra (positive ion detection,
2,5-dihydroxybenzoic acid matrix) were obtained on a Bruker
AutoflexTM III Smartbeam mass spectrometer. Samples were pre-
pared by the dried drop technique. Solutions of a matrix and ana-
lyte were mixed at a ratio of 50: 1 to 100: 1, and a drop of the
Fig. 1. The X-ray crystal structure of compound (9). Atoms are represented by thermal
displacement ellipsoids (50% probability level).
Scheme 3. Multicomponent condensation between adamantylamines, formaldehyde, and 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins.
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

4
E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
resulting mixture was applied to a target and dried in a stream of
warm air. The sample was transferred from the target to the gas
phase by laser pulses (200 pulses at a frequency of 100 Hz) using a
4.1.2. 2,7-Dibutyl-4,9-dimethyl-2,3а,5а,7,8а,10а-hexaaza-
perhydropyrene (5) and 2,7-dibutyl-4,10-dimethyl-2,3а,5а,7,8а,10а-
hexaazaperhydropyrene (6)
solid state UV laser (
l
355 nm). The elemental analyses were ob-
Yield 0.30 g (83%), R
film) 2955e2869 (br),1460,1214 cm
f
(MeOH) 0.60; white powder, nmax (liquid
ꢁ1
tained on a Carlo Erba 1106 analyzer. The melting points were
determined on a PHMK 80/2617 melting point apparatus. The re-
action progress was monitored by TLC using Sorbfil plates (PTSH-
AF-V), visualization with iodine vapor. Column chromatography
;
d
H
(500.17 MHz, CDCl
3
) 0.89
0
00
(12H, t, J 9 Hz, CH
3
, H-4 ,4 ), 0.98 (12Н, br. s, СН , Н-11,12), 1.31 (8Н,
3
0 00 0 00
q, J 9 Hz, СН
(4H, m, CH , H
2.36e2.44 (4H, m, CH
Н-4,10; 2Н, СН, Н-10b,10с), 2.49 (1H, d, J 9 Hz, CH, Н-10b),
2
, Н-3 ,3 ), 1.40 (8Н, q, J 9 Hz, СН , Н-2 ,2 ), 1.92e1.99
2
3
2
a
-5,10 and H
, H
a
-5,9), 2.29 (1Н, d, J 9 Hz, СН, Н-10с),
-5,10 and H -5,9; 4Н, СН, Н-4,9 and
was performed on KSK silica gel (100e200
mm). 2,6(7)-Dimethyl-
2
b
b
3
1
,4,5,8-tetraazadecalins (1, 2) were obtained as described previ-
15
0
00
2
ously. X-ray diffraction analysis was performed on an automatic
2.66e2.77 (8H, m, CH
2
, H-1 ,1 ), 2.85 (4H, t, Jab 13 Hz, CH
2.95 (4H, dd, Jab 12.5 and 12.5 Hz, CH , Н -1,6), 3.58 (4H, dd,
12.5 and 12.5 Hz, CH , Н -1,6), 3.95 (4H, d, Jba 12.5 Hz, CH
(125.78 MHz, CDCl ) 14.0 (C-4 , C-4 ), 16.7 and 17.0 (С-11, C-12),
2
, Н
а
-3,8),
2
2
four-circle diffractometer XCalibur Eos (graphite monochromator,
2
а
J
ba
ꢀ
2
MoK
a
radiation,
l
0.71073 Å, w-scanning, 2
q
max 62 ). The data
2
b
2
, Н
b
-3,8);
0
00
were acquired and processed with the aid of CrysAlisPro, version
.171.36.20 (Oxford Diffraction Ltd.). The structure was solved by
d
C
3
0 00 0 00
1
20.4 (C-3 , C-3 ), 30.4 (C-2 , C-2 ), 51.2 and 51.4 (C-4, C-9 and C-4, C-
0
00
the direct method and refined by the full-matrix least-squares
procedure in anisotropic approximation for non-hydrogen atoms.
Hydrogen atoms were localized from the Fourier difference maps
and were refined with fixed thermal and positional parameters. The
calculations were performed using SHELX97. The crystallographic
data, coordinates of atoms, and geometric parameters for com-
pound (9) were deposited at the Cambridge Crystallographic Data
Centre (entry no. CCDC 1551102). The copies of the data are avail-
able free on demand from CCDC, 12, Union Road, Cambridge, CB2
10), 52.4 and 52.5 (C-1 , C-1 ), 55.9 and 56.2 (C-5, C-10 and C-5, C-
9), 70.6 and 70.8 (C-3, C-8), 74.0 and 74.2 (C-1, C-6), 82.2 (C-10b),
82.7 (C-10b, C-10c), 83.1 (C-10с); MALDI TOF/TOF: m/z (Irel, %): 363
þ
[MeH] (100).
2
0
4.1.3. 2,7-Diisopropyl-4,9-dimethyl-2,3а,5а,7,8а,10а-hexaaza-
perhydropyrene (7)
Yield 0.26 g (77%), R
184e186 C; nmax (liquid film) 2965e2875 (br), 1464, 1214 cm
f
(MeOH) 0.63, white powdered crystals, mp
о
ꢁ1
; d
H
1
EZ, UK (fax: þ44 1223 336033, e-mail: deposit@ccdc.cam.ac.uk) or
(500.17 MHz, CDCl
3
) 1.01 (6H, d, J 7.5 Hz, CH
3
, H-11,12),1.10 (12H, d, J
ab 13 Hz, CH , H -5,10),
b
-5,10; 4Н, СН, Н-4,9,10b,10с), 2.86 (2H, d,
0
00
0
00
2
through http://www.ccdc.cam.ac.uk/data_request/cif.
8 Hz, CH
3
, H-2 ,2 ,3 ,3 ), 1.99 (2H, t,
J
2
а
2
J
.38e2.48 (2H, m, CH
2
, H
2
2
ab 12.5 Hz, CH
2
, H
а
-3,8), 2.94 (2H, d,
J
ab 12.5 Hz, CH
2
, H
, H
a
-1,6),
-1,6),
0
00
2
3
.17e3.26 (2Н, m, СН, Н-1 ,1 ), 3.78 (2H, d, Jba 12.5 Hz, CH
2
b
2
4
(
.1. Heterocyclization of 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins
1, 2) with N,N-bis(methoxymethyl)-N-alkylamines (General
method)
4.17 (2H, d, Jba 12.5 Hz, CH
2
, H
b
-3,8);
d
C
(125.78 MHz, CDCl
3
) 16.6
0
00
0
00
0
00
(С-11, C-12), 20.5 and 20.9 (C-2 , C-2 , C-3 , C-3 ), 48.9 (C-1 , C-1 ),
51.4 (C-4, C-9), 56.5 (С-5, C-10), 68.1 (C-3, C-8), 71.4 (С-1, C-6), 82.2
þ
(C-10b, C-10c); MALDI TOF/TOF: m/z (Irel, %): 335 [MeH] (100).
A mixture of the corresponding N,N-bis(methoxymethyl)-N-
alkylamine (2.00 mmol), obtained in situ by the reported proced-
Anal. Calcd. (%) for C18
64.19; H, 10.75; N, 24.92.
36 6
H N : С, 64.24; H, 10.78; N, 24.97; found: С,
14
ure, in MeOH (10 mL) with SmCl
3 2
$6H O (0.018 g, 0.05 mmol) was
stirred for 30 min at room temperature. Next, 2,6(7)-dimethyl-
4.1.4. 2,7-Ditertbutyl-4,9-dimethyl-2,3а,5а,7,8а,10а-hexaaza-
1
,4,5,8-tetraazadecalins (1, 2) (0.17 g, 1.00 mmol) in H
2
O (1 mL)
perhydropyrene (8)
ꢀ
were added to the mixture. The mixture was stirred at 20 C for 3 h
and evaporated. The residue was separated by column chroma-
Yield 0.29 g (79%), R
f
(MeOH) 0.64, white powdered crystals, mp
о
ꢁ1
185e187 C; nmax (liquid film) 2952e2866 (br), 1463, 1261 cm
; d
H
tography on silica gel (SiO
2
) with MeOH as the eluent, and the
3 3
(500.17 MHz, CDCl ) 1.03 (6H, d, J 7.5 Hz, CH , H-11,12), 1.13 (18H, br.
0
00
0
00
0
00
2
heterocycles (3e8) were isolated. Compounds (7) and (8) were
obtained as white powdered crystals (recrystallized from MeOH).
The final products (3e8) were identified by spectral methods.
s, CH
3
, H-2 ,2 ,3 ,3 ,4 ,4 ), 2.05 (2H, t, CH
2
, Jab 13 Hz, H
, H -5,10; 2H, CH,
-3,8), 2.69 (2H, d,
, H -1,6), 4.26 (2H,
а
-5,10), 2.36
(2H, br. s, CH, H-10b,10с), 2.42e2.55 (2H, m, CH
2
b
2
2
H-4,9), 2.58 (2H, d,
0.5 Hz, CH , H
d, Jba 10.5 Hz, CH
J
ab 10.5 Hz, CH
2
, H
а
J
ab
2
1
2
a
-1,6), 3.86 (2H, d, Jba 10.5 Hz, CH
2
b
2
2
00
, H
b
-3,8);
d
00
C
(125.78 MHz, CDCl
3
) 16.7 (С-11, C-
0
0
0
00
0
1
2), 27.0 (C-2 , C-2 , C-3 , C-3 , C-4 , C-4 ), 51.9 (C-4, C-9), 52.9 (C-1 ,
0
0
4
.1.1. 2,7-Dipropyl-4,9-dimethyl-2,3
perhydropyrene (3) and 2,7-dipropyl-4,10-dimethyl-
,3 ,5 ,7,8 ,10 -hexaazaperhydropyrene (4)
Yield 0.27 g (81%), R (MeOH) 0.61; white powder, nmax (liquid
film) 2956e2872 (br), 1457, 1211 cm
а,5
а,7,8а,10а-hexaaza-
C-1 ), 57.0 (С-5, C-10), 66.4 (C-3, C-8), 69.8 (С-1, C-6), 82.4 (C-10b,
þ
C-10c); MALDI TOF/TOF: m/z (Irel, %): 403 [MþК] (90), 387
þ
þ
2
а
а
а
а
[MþNa] (80), 363 [MeH] (100). Anal. Calcd. (%) for C20
40 6
H N : С,
f
65.89; H, 11.06; N, 23.05; found: С, 65.82; H, 11.02; N, 23.00.
ꢁ
1
;
d
H
(500.17 MHz, CDCl
, H-3 ,3 ), 0.99 (12Н, br. s, СН , Н-11,12), 1.47
, Н-2 ,2 ), 1.94e2.04 (4H, m, CH , H -5,10 and
-5,9), 2.31 (1Н, d, J 9 Hz, СН, Н-10с), 2.35e2.45 (4H, m, CH , H
,10 and H -5,9; 4Н, СН, Н-4,9 and Н-4,10; 2Н, СН, Н-10b,10с), 2.51
3
) 0.90
0
00
00
(
(
12H, t, J 8.5 Hz, CH
8Н, q, J 9.5 Hz, СН
3
3
4.2. Ring transformation reaction of 1,3,5-tricycloalkyl-1,3,5-
triazines with 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins (1, 2)
(General method)
0
2
2
a
3
H
5
a
2
b
-
b
3
0 00
(
1H, d, J 9 Hz, CH, Н-10b), 2.65e2.75 (8H, m, CH
2
, H-1 ,1 ), 2.87 (4H,
A round bottom flask equipped with a magnetic stir bar was
charged with MeOH (10 mL), the corresponding 1,3,5-tricycloalkyl-
2
2
t, Jab 13 Hz, CH
,6), 3.60 (4H, dd, Jba 12.5 and 12.5 Hz, CH
2.5 Hz, CH , Н -3,8); (125.78 MHz, CDCl
and 17.0 (С-11, C-12), 21.4 (C-2 , C-2 ), 51.3 and 51.4 (C-4, C-9 and C-
2
, Н
а
-3,8), 2.98 (4H, dd, Jab 12.5 and 12.5 Hz, CH , Н
2
а
-
2
2
1
1
2
, Н
b
-1,6), 3.97 (4H, d, Jba
1,3,5-triazine (2.00 mmol), obtained in situ by the reported pro-
0
00
8
2
b
d
C
3
) 11.8 (C-3 , C-3 ), 16.7
cedure and NiCl
2
$6H
2
O (0.012 g, 0.05 mmol). The mixture was
0
00
stirred at room temperature for 30 min. Next, 2,6(7)-dimethyl-
0
00
4
, C-10), 54.6 and 54.8 (C-1 , C-1 ), 55.9 and 56.2 (C-5, C-10 and C-5,
1,4,5,8-tetraazadecalins (1, 2) (0.17 g, 1.00 mmol) in H
were added to the mixture. The mixture was stirred at 20 C for 3 h
and evaporated. The residue was separated by column chroma-
2
O (1 mL)
ꢀ
C-9), 70.6 and 70.8 (C-3, C-8), 74.1 and 74.2 (C-1, C-6), 82.2 (C-10b),
8
2.7 (C-10b, C-10c), 83.2 (C-10с); MALDI TOF/TOF: m/z (Irel, %): 335
þ
[
MeH] (100).
2
tography on silica gel (SiO ) with MeOH as the eluent. Compound
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
5
о
ꢁ1
d
(9) was obtained as colorless crystals (recrystallized from MeOH).
187e189 C; nmax (liquid film) 2921e2852 (br), 1451, 1202 cm
;
H
Compounds (10e14) were obtained as white powdered crystals.
The final products (9e14) were identified by spectral methods.
(500.17 MHz, CDCl
3
) 1.01 (6H, d, J 7.5 Hz, CH
3
, H-11,12), 1.35e1.45
0
00
0
00
0
00
0
00
(4H, m, CH
2
, H
a
-3 ,3 ,6 ,6 ), 1.47e1.57 (12H, m, CH
2
, Н-4 ,4 ,5 ,5 ;
0
00
0
00
0
00
0
00
H
a
-2 ,2 ,7 ,7 ), 1.59e1.69 (4H, m, CH
2
, H
b
-3 ,3 ,6 ,6 ), 1.80e1.90 (4H,
-2 ,2 ,7 ,7 ), 2.00 (2H, t, Jab 13 Hz, CH , Н -5,10), 2.37 (2H,
br. s, CH, Н -10b,10с), 2.39e2.49 (2H, m, CH, H-4,9; 2Н, СН , H
5,10), 2.81 (2H, d, ab 12 Hz,
0
00
0
00
2
4.2.1. 2,7-Dicyclopropyl-4,9-dimethyl-2,3а,5а,7,8а,10
а-hexaaza-
m, CH
2
, H
b
2
а
perhydropyrene (9)
Yield 0.26 g (79%), R
of prisms, mp 180e182 C; nmax (liquid film) 2990e2875 (br), 1450,
b
2
b
-
2
2
f
о
(MeOH) 0.61, colorless crystals in the form
J
ab 12 Hz, CH
2 а
, H -3,8), 2.88 (2H, d, J
0
00
2
CH
CH
2
, H
, H
а
-1,6), 2.91e2.98 (2Н, m, СН, Н-1 ,1 ), 3.70 (2H, d, Jba 12 Hz,
ꢁ
00
1
2
1
2
CH
215 cm
;
d
H
(500.17 MHz, CDCl
,2 ,3 ,3 ), 1.03 (6H, d, J 7.5 Hz, CH , H-11,12), 2.02 (2H, t, Jab 13 Hz,
-5,10), 2.38e2.58 (2H, m, CH -5,10; 6Н, СН,
-3,8), 2.95 (2H, d,
3
) 0.42e0.48 (8H, m, CH
2
, H-
2
b
-1,6), 4.07 (2H, d, Jba 12 Hz, CH
2
, H
b
-3,8);
d
C
(125.78 MHz,
0
00
0
2
0
00
0
00
3
CDCl
3
) 16.7 (С-11, C-12), 24.7 and 24.8 (C-3 , C-3 , C-6 , C-6 ), 28.4
0
00
0
00
0
00
0
00
2
,
H
а
2
,
H
b
(C-4 , C-4 , C-5 , C-5 ), 31.0 and 31.5 (C-2 , C-2 , C-7 , C-7 ), 51.6 (C-
0
00
2
0
00
Н-1 ,1 ,4,9,10b,10c), 2.89 (2H, d, Jab 12 Hz, CH
ab 12 Hz, CH
2
, H
а
4, С-9), 56.6 (C-5, С-10), 60.1 (C-1 , C-1 ), 68.4 (C-3, С-8), 71.5 (C-1,
С-6), 82.6 (C-10b, C-10c); MALDI TOF/TOF: m/z (Irel, %): 443 [MeH]
(100). Anal. Calcd. (%) for C26
found: С, 70.16; H, 10.82; N, 18.81.
2
2
þ
J
2
, H
а
-1,6), 3.72 (2H, d, Jba 12 Hz, CH , H
2
b
-1,6), 4.07 (2H,
) 6.4 and 6.5 (C-2 ,
2
0
d, Jba 12 Hz, CH
, H
2 b
-3,8);
d
C
(125.78 MHz, CDCl
3
48 6
H N : С, 70.22; H, 10.88; N, 18.90;
0
0
0
00
0
00
C-2 , C-3 , C-3 ), 16.7 (С-11, C-12), 33.3 (C-1 , C-1 ), 51.6 (C-4, C-9),
5
6.3 (С-5, C-10), 71.1 (C-3, C-8), 74.4 (С-1, C-6), 82.6 (C-10b, C-10c);
þ
MALDI TOF/TOF: m/z (Irel, %): 333 [MþH] (100). Anal. Calcd. (%) for
4.2.5. 2,7-Dicyclooctyl-4,9-dimethyl-2,3а,5а,7,8а,10а-hexaaza-
perhydropyrene (13)
C
2
H
18 32
N
6
: С, 65.02; H, 9.70; N, 25.28; found: С, 64.97; H, 9.67; N,
5.22. Crystal data for (9): C18 1,
, M ¼ 332.50, triclinic, P
¼ 61.94 (3),
¼ 87.28 (2), V ¼ 467.1 (2) Å , T ¼ 298 (2)K,
H
32
N
6
ˉ
Yield 0.41 g (87%), R
169e171 C; nmax (liquid film) 2920e2848 (br), 1468, 1214 cm
f
(MeOH) 0.61, white powdered crystals, mp
о
ꢁ1
a ¼ 7.324 (2) Å, b ¼ 8.805 (2) Å, c ¼ 8.952 (3) Å,
a
; d
H
3
b
¼ 68.16 (3),
calcd ¼ 1.182 g/cm , Z ¼ 1, reflection collected ¼ 3379, independent
(I), 1332 reflec-
¼ 0.1598, S ¼ 0.900; CCDC 1551102.
g
(500.17 MHz, CDCl
3
) 1.01 (6H, d, J 7.5 Hz, CH
3
, H-11,12), 1.40e1.60
3
0
00
0
00
0
00
0
00
0
00
0
00
0
00
D
(20H, m, CH
(4H, m, CH
2
, H
, H
a
-2 ,2 ,3 ,3 ,7 ,7 ,8 ,8 ; Н-4 ,4 ,5 ,5 ,6 ,6 ),1.65e1.75
0
00
0
00
0 00 0 00
reflection ¼ 2093 (Rint ¼ 0.0135), R values [I > 2
s
2
b
-3 ,3 ,7 ,7 ), 1.78e1.88 (4H, m, CH
1.99 (2H, t, Jab 13 Hz, CH , H -5,10), 2.37 (2H, br. s, CH, Н-10b,10с),
.40e2.50 (2Н, m, СН , H -5,10; 2H, CH, H-4,9), 2.81 (2H, d,
12 Hz, CH , H -3,8), 2.88 (2H, d, Jab 12 Hz, CH
(2Н, m, СН, Н-1 ,1 ), 3.71 (2H, d, Jba 12 Hz, CH
2 b
, H -2 ,2 ,8 ,8 ),
2
tion]: R
1
¼ 0.0477, wR
2
2
а
2
2
2
b
J
ab
2
4
.2.2. 2,7-Dicyclopentyl-4,9-dimethyl-2,3 ,5 ,7,8 ,10 -hexaaza-
а
а
а
а
2
а
2
а
, H -1,6), 2.95e3.05
0
00
2
perhydropyrene (10)
2
, H -1,6), 4.09 (2H, d,
b
2
Yield 0.31 g (81%), R
28e230 C; nmax (liquid film) 2955e2858 (br), 1459, 1209 cm
f
(MeOH) 0.63, white powdered crystals, mp
J
ba 12 Hz, CH
2
, H
00
b
-3,8);
d
C
(125.78 MHz, CDCl
3
) 16.7 (С-11, C-12),
о
ꢁ1
0
0
00
0
00
0
2
;
24.4 (C-3 , C-3 , C-7 , C-7 ), 26.1 (C-5 , C-5 ), 27.2 and 27.3 (C-4 , C-
4 , C-6 , C-6 ), 29.0 and 29.3 (C-2 , C-2 , C-8 , C-8 ) 51.5 (C-4, С-9),
00 0 00 0 00 0 00
d
H
(500.17 MHz, CDCl
3
) 1.01 (6H, d, J 7 Hz, CH
3
, H-11,12), 1.30e1.40
0
00
0
00
0
00
0
00
0
00
(
4H, m, CH
2
, H
а
-2 ,2 ,5 ,5 ), 1.54e1.62 (4H, m, CH
2
, H
-3 ,3 ,4 ,4 ), 1.85e1.92 (4H, m, CH
,2 ,5 ,5 ), 1.97 (2H, t, Jab 13 Hz, CH , H -5,10), 2.35e2.48 (2H, m,
, H -5,10; 4Н, СН, Н-4,9,10b,10с), 2.86 (2H, d, Jab 12.5 Hz, CH
а
-3,8), 2.94 (2H, d, Jab 12.5 Hz, CH -1,6), 3.32e3.36 (2Н, m, СН,
а
-3 ,3 ,4 ,4 ),
56.6 (C-5, С-10), 58.3 (C-1 , C-1 ), 68.4 (C-3, С-8), 71.6 (C-1, С-6),
0
00
0
00
þ
1
2
CH
.65e1.73 (4H, m, CH
2
, H
b
2
, H
b
-
82.7 (C-10b, C-10c); MALDI TOF/TOF: m/z (Irel, %): 511 [MþК] (100),
0
00
0
00
2
þ
þ
2
а
495 [MþNa] (50), 471 [MeH] (10). Anal. Calcd. (%) for C28
52 6
H N :
2
2
b
2
,
С, 71.14; H, 11.09; N, 17.77; found: С, 71.08; H, 11.02; N, 17.72.
2
H
а
2
, H
Н-1 ,1 ), 3.72 (2H, d, 2Jba 12.5 Hz, CH
0
00
, H
(125.78 MHz, CDCl
-1,6), 4.11 (2H, d,
) 16.7 (С-11, C-12), 23.9
2
J
4.2.6. 2,7-Dibicyclo[2.2.1]hept-2-yl-4,9-dimethyl-2,3а,5а,7,-8а,10а-
hexaazaperhydropyrene (14)
2
b
ba
1
2.5 Hz, CH
2
, H
b
-3,8);
d
C
3
0
00
0
00
0
00
0
00
and 24.0 (C-3 , C-3 , C-4 , C-4 ), 31.2 (C-2 , C-2 , C-5 , C-5 ), 51.3 (C-
4
Yield 0.35 g (79%), R
239e241 C; nmax (liquid film) 2953e2869 (br),1450,1214 cm
f
(MeOH) 0.67, white powdered crystals, mp
0
00
о
ꢁ1
, C-9), 56.4 (С-5, C-10), 60.0 (C-1 , C-1 ), 69.8 (C-3, C-8), 73.4 (С-1,
; d
H
þ
C-6), 82.6 (C-10b, C-10c); MALDI TOF/TOF: m/z (Irel, %): 387 [MeH]
100). Anal. Calcd. (%) for C22
found: С, 67.93; H, 10.33; N, 21.57.
(500.17 MHz, CDCl
3
) 0.95e1.12 (6H, m, CH
3 2 а
, H-11,12; 6Н, СН , Н -
0
00
0
00
0
00
0
00
0
00
0
00
(
40
H N
6
: С, 68.00; H, 10.38; N, 21.62;
3 ,3 ,6 ,6 ,7 ,7 ), 1.30e1.55 (10H, m, CH
2
,
H
b
-3 ,3 ,6 ,6 ,7 ,7 ;
0
0
00
00
Н-5 ,5 ), 1.92e2.04 (2H, m, CH
2
0
, H
а
-5,10), 2.24 (2H, br. s, CH,
00
Н-4 ,4 ), 2.30 (2H, br. s, CH, Н-2 ,2 ), 2.60e2.78 (2Н, m, СН
2
, H
b
-
0
00
4.2.3. 2,7-Dicyclohexyl-4,9-dimethyl-2,3а,5а,7,8а,10
а-hexaaza-
5,10; 4H, CH, H-4,9,10b,10с), 2.70e2.82 (2Н, m, СН, Н-1 ,1 ; 4Н, СН
-1,3,6,8), 3.70e3.82 (2H, m, CH , H -1,6), 4.12e4.20 (2H, m, CH
2
2
,
,
perhydropyrene (11)
Н
а
2
b
0
00
Yield 0.38 g (92%), R
38e240 C; nmax (liquid film) 2922e2859 (br),1444,1214 cm
f
(MeOH) 0.63, white powdered crystals, mp
H
b
-3,8);
d
C
(125.78 MHz, CDCl
3
00
) 16.8 (С-11, C-12), 27.6 (C-6 , C-6 ),
о
ꢁ1
0
00
0
0
00
0
00
2
;
d
H
28.4 (C-7 , C-7 ), 35.2 (C-3 , C-3 ), 36.3 (C-4 , C-4 ) 37.4 (C-5 , C-5 ),
38.4 (C-2 , C-2 ), 51.5 (C-4 , C-9), 56.5 (С-5, С-10), 62.5 (C-1 , C-1 )
0
00
0
0
00
(
500.17 MHz, CDCl
3
) 1.02 (6H, d, J 7.5 Hz, CH
3
, H-11,12), 1.08e1.18
0
00
0
00
0
00
(
6H, m, CH
2
, H
a
-2 ,2 ,4 ,4 ,6 ,6 ), 1.24e1.34 (4H, m, CH
2
, H
, H
-2 ,2 ,6 ,6 ),
a
-
-
68.8 (C-3, С-8), 72.6 (C-1, С-6), 82.5 (C-10b, C-10c); MALDI TOF/
0
0
00
00
0
0
00
00
0
00
þ
3
3
2
,3 ,5 ,5 ), 1.62 (2H, br. s, CH
2
, H
,3 ,5 ,5 ), 1.93e2.03 (6H, m, CH
, Н -5,10; 4Н, СН, H-4,9,10b,10с), 2.80e2.86
b
-4 ,4 ), 1.72e1.80 (4H, m, CH
2
b
00
TOF: m/z (Irel, %): 439 [MeH] (100). Anal. Calcd. (%) for C26
H
44
N
6
:
0
00
0
2
,
Н
а
-5,10;
H
b
С, 70.86; H, 10.06; N, 19.08; found: С, 70.77; H, 10.01; N, 19.02.
.36e2.48 (2H, m, CH
2
b
0
00
2
(
2H, m, CH, H-1 ,1 ), 2.88 (2H, d, Jab 12.5 Hz, CH
2
, H
а
-3,8), 2.96 (2H,
, H -1,6), 4.19
4.3. Multicomponent condensation of adamantylamines with
formaldehyde and 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins (1, 2)
(General method)
2
2
d, Jab 12.5 Hz, CH, H
а
-1,6), 3.80 (2H, d, Jba 12.5 Hz, CH
2
b
2
(
2H, d, Jba 12.5 Hz, CH
2
, H
b
-3,6);
d
C
(125.78 MHz, CDCl
3
) 16.7 (С-11,
0
00
0
00
0
00
C-12), 25.3 and 25.3 (C-3 , C-3 , C-5 , C-5 ), 26.0 (C-4 , C-4 ), 30.5
3
1
и
0
00
0
00
0.9 (C-2 , C-2 , C-6 , C-6 ), 51.4 (C-4, С-9), 56.4 (C-5, С-10), 57.0 (C-
A round bottom flask equipped with a magnetic stir bar was
0
00
, C-1 ), 67.7 (C-3, С-8), 71.1 (C-1, С-6), 82.8 (C-10b, C-10c); MALDI
charged with MeOH (10 mL), the corresponding adamantylamine
þ
20
TOF/TOF: m/z (Irel, %): 415 [MeH] (100). Anal. Calcd. (%) for
(2.00 mmol), formaldehyde (0.45 mL, 4.00 mmol) and zeolite Y
C
2
24
H
0.12.
44
N
6
: С, 69.18; H, 10.64; N, 20.18; found: С, 69.11; H, 10.60; N,
(10 wt%). Next, 2,6(7)-dimethyl-1,4,5,8-tetraazadecalins (1, 2)
(0.17 g, 1.00 mmol) in H
2
O (1 mL) were added to the mixture. The
ꢀ
mixture was stirred at 20 C for 3 h. The white precipitate was
filtered and washed twice with MeOH (5 mL). Compounds (15e19)
were obtained as white powdered crystals (recrystallized from
4.2.4. 2,7-Dicycloheptyl-4,9-dimethyl-2,3
а,5а,7,8а,10а-hexaaza-
perhydropyrene (12)
Yield 0.37 g (83%), R
f
(MeOH) 0.60, white powdered crystals, mp
3
CHCl ). The final products (15e19) were identified by spectral
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

6
E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
methods.
4.3.4. 2,7-Bis(3,5-dimethyl-1-adamantyl)-4,9-dimethyl-2,3
а,5а,-
7
,8 ,10 -hexaazaperhydropyrene (18)
а
а
Yield 0.31 g (53%), R
255e257 C; nmax (liquid film) 2923e2853 (br), 1455, 1207 cm
f
(CHCl
3
) 0.76, white powdered crystals, mp
о
ꢁ1
4.3.1. 2,7-Di(1-adamantyl)-4,9-dimethyl-2,3а,5а,7,8а,10
а-hexa-
;
0 00 0 00
3
, Н-11 ,11 ,12 ,12 ), 1.05
azaperhydropyrene (15)
d
H
(500.17 MHz, CDCl
3
) 0.85 (12H, br. s, CH
0 00
2
, Н-11,12), 1.08e1.14 (4H, m, CH , Н-9 ,9 ), 1.28
Yield 0.35 g (67%), R
50e252 C; nmax (liquid film) 2922e2852 (br), 1457, 1216 cm
f
(CHCl
3
) 0.75, white powdered crystals, mp
(6H, d, J 6 Hz, CH
3
0
о
ꢁ1
00
0
00
0
00
0
00
2
;
d
H
(8Н, br. s, СН
1.64 (4H, br. s, CH
2.14 (2H, br. s, CH, Н-3 ,3 ), 2.35 (2H, br. s, CH, Н-10b,10с), 2.42e2.48
2
, Н-4 ,4 ,10 ,10 ), 1.34e1.45 (8H, m, CH
2
, Н-6 ,6 ,7 ,7 ),
0
00
2
(
(
2
500.17 MHz, CDCl
3
) 1.03 (6H, d, J 6 Hz, CH
3
, Н-11,12), 1.59e1.67
, Н-4 ,4 ,9 ,9 ,10 ,10 ), 1.79 (12H, br. s, CH , H-
-5,10), 2.07 (6H, br. s,
2
, Н-2 ,2 ), 2.04 (2H, t,
J
ab 10 Hz, CH , H -5,10),
2
а
0
00
0
00
0
00
0
00
12H, m, CH
2
2
0
00
0
00
0
00
2
2
,2 ,6 ,6 ,7 ,7 ), 2.01 (2H, t, Jab 11 Hz, CH
2
, H
а
(2H, m, CH, Н-4,9), 2.50e2.53 (2H, m, CH
2
, Н
b
-5,10), 2.67 (2H, d, Jab
, H -1,6), 3.93 (2H, d,
ba 8.5 Hz, CH
0
00
0
00
0
00
2
CH, Н-3 ,3 ,5 ,5 ,8 ,8 ), 2.35 (2H, br. s, CH, Н-10b,10с), 2.38e2.45
8.5 Hz, CH
2
, H
ba 8.5 Hz, CH
(125.78 MHz, CDCl
а
-3,8), 2.77 (2H, d, Jab 8.5 Hz, CH
2
а
2
2
2
(
2Н, m, СН, H-4,9), 2.48e2.51 (2Н, m, СН, Н
b
-5,10), 2.69 (2H, d, Jab
, H
ba 9 Hz, CH
J
2
, H
b
-1,6), 4.32 (2H, d,
J
2
00
, H
b
-3,8);
d
C
0
2
2
0
9
9
(
Hz, CH
2
, H
а
-3,8), 2.80 (2H, d, Jab 9 Hz, CH
2
а
-1,6), 3.93 (2H, d, Jba
, H -3,8);
3
) 16.8 (С-11, C-12), 30.3 (C-3 , C-3 ), 30.6 (C-11 ,
2
00 0 00 0 00 0 00 0 00
Hz, CH
2 b
, H -1,6), 4.34 (2H, d,
J
2
00
b
0
d
C
C-11 , C-12 , C-12 ), 32.3 (C-5 , C-5 , C-8 , C-8 ), 38.3 (C-2 , C-2 ),
0
00
0 00 0 00 0 00 0 00
43.0 (C-4 , C-4 , C-10 , C-10 ), 45.8 and 45.9 (C-6 , C-6 , C-7 , C-7 ),
125.78 MHz, CDCl
3
) 16.8 (С-11, C-12), 29.6 (C-3 , C-3 , C-5 , C-5 , C-
0
00
0
00
0
00
0
00
0
00
0
00
0
00
8
, C-8 ), 36.8 (C-4 , C-4 , C-9 , C-9 , C-10 , C-10 ), 40.0 (C-2 , C-2 ,
50.9 (C-9 , C-9 ), 51.9 (C-4, C-9) 55.3 (C-1 , C-1 ), 57.0 (C-5, C-10),
0
00
0
00
0
00
C-6 , C-6 , C-7 , C-7 ), 51.9 (C-4, C-9) 53.5 (C-1 , C-1 ), 57.0 (C-5, C-
0), 65.1 (C-3, C-8), 68.5 (С-1, С-6), 82.8 (C-10b, C-10c); MALDI TOF/
65.4 (C-3, C-8), 68.8 (С-1, С-6), 82.7 (C-10b, C-10c); MALDI TOF/
þ
1
TOF: m/z (Irel, %): 575 [MeH] (100). Anal. Calcd. (%) for C36
60
H N
6
: С,
þ
þ
þ
TOF: m/z (Irel, %): 559 [MþK] (40), 543 [MþNa] (100), 519 [MeH]
60). Anal. Calcd. (%) for C32 : С, 73.80; H, 10.06; N, 16.14;
found: С, 73.74; H, 10.02; N, 16.09.
74.95; H, 10.48; N, 14.57; found: С, 74.87; H, 10.45; N, 14.50.
(
52 6
H N
4
.3.5. 2,7-Bis(1-hydroxy-1-adamantyl)-4,9-dimethyl-2,3
а,5а,-
7
,8 ,10 -hexaazaperhydropyrene (19)
а
а
Yield 0.28 g (50%), R
46e248 C; nmax (liquid film) 2922e2854 (br),1461,1223 cm
f
(CHCl
3
) 0.69, white powdered crystals, mp
4
.3.2. 2,7-Di(2-adamantyl)-4,9-dimethyl-2,3
а
,5
а
,7,8
а
,10
а
-hexa-
о
ꢁ1
2
(
CH
; d
H
azaperhydropyrene (16)
500.17 MHz, CDCl
3
) 1.03 (6H, d, J 6 Hz, CH
3
, Н-11,12), 1.50 (4H, br. s,
, Н-4 ,4 ,9 ,9 ), 1.68e1.80 (12H,
Yield 0.31 g (59%), R
49e251 C; nmax (liquid film) 2923e2853 (br), 1461, 1211 cm
f
(CHCl
3
) 0.73, white powdered crystals, mp
0
00
0
2
00
0
00
2
, Н-10 ,10 ), 1.65 (8H, br. s, CH
2
о
ꢁ1
2
;
d
H
0 00 0 00 0 00
m, CH
.27 (6H, br. s, CH, Н-5 ,5 ,8 ,8 ,10b,10c), 2.37e2.43 (2H, m, CH,
2
, Н-2 ,2 ,6 ,6 ,7 ,7 ), 1.99 (2Н, t, Jab 10.5 Hz, СН , Н -5,10),
2
а
(
1
500.17 MHz, CDCl
Hz, CH
3
) 0.99 (6H, d, J 6 Hz, CH
3
, Н-11,12), 1.41 (4H, d, J
0
00
0
00
2
0
00
0
00
1
2
,
Н
а
-7 ,7 ,9 ,9 ), 1.68e1.88 (12H, m, CH
2
2
2
,
,
,
2
2
Н-4,9), 2.46 (2H, t, Jba 10.5 Hz, CH
2
, H
-3,8), 2.82 (2H, d, Jab 9 Hz, CH , H
ba 9 Hz, CH
b
-5,10), 2.75 (2H, d, Jab 9 Hz,
0
00
0
00
0
00
0
00
0
00
Н-3 ,3 ,5 ,5 ,10 ,10 ; 4Н, СН, Н-4 ,4 ,8 ,8 ), 1.92e2.08 (6H, m, CH
Н
H
2
2
2
CH
CH
2
, H
, H
а
2
а
-1,6), 3.92 (2H, d, Jba 9 Hz,
0
00
0
00
0
00
0
00
b
-7 ,7 ,9 ,9 ; H
a
-5,10; 4Н, СН, Н-2 ,2 ,6 ,6 ), 2.43 (2H, br. s, CH
2
2
b
-1,6), 4.32 (2H, d,
J
2
00
, H
b
-3,8);
d
00
C
(125.78 MHz,
2
b
-5,10; 4Н, СН, Н-4,9,10b,10с), 2.82 (2H, d, Jab 10 Hz, CH
2
, H
а
-3,8),
0
0
0
CDCl
3
) 17.0 (С-11, C-12), 30.8 (C-5 , C-5 , C-8 , C-8 ), 35.2 (C-10 , C-
2
0
00
.89 (2H, d, Jab 10 Hz, CH
2
, Н
а
-1,6), 3.08 (2H, br. s, CH, Н-1 ,1 ), 3.80
00
0
00
0
00
0
00
0
00
1
(
(
0 ), 38.9 (C-6 , C-6 , C-7 , C-7 ), 44.4 (C-4 , C-4 , C-9 , C-9 ), 48.0
2
2
(
2H, d, Jba 10 Hz, CH
2
, H
b
-1,6), 4.20 (2H, d, Jba 10 Hz, CH
2
, H
b
-3,8);
0
0
0
0
0
0
C-2 , C-2 ), 52.0 (C-4, C-9), 56.5 (C-5, C-10), 57.1 (C-1 , C-1 ), 65.3
0
00
d
C
(125.78 MHz, CDCl
3
) 16.8 (С-11, C-12), 27.3 and 27.6 (C-4 , C-4 ,
0
00
C-3, C-8), 68.6 (С-1, С-6), 69.9 (C-3 , C-3 ), 83.1 (C-10b, C-10c);
MALDI TOF/TOF: m/z (Irel, %): 551 [MeH] (100). Anal. Calcd. (%) for
H N O : С, 69.53; H, 9.48; N, 15.20; O, 5.79; found: С, 69.48; H,
32 52 6 2
.43; N, 15.14.
0
00
0
00
0
00
0
00
C-8 , C-8 ), 28.9 (C-2 , C-2 , C-6 , C-6 ), 31.2 and 31.2 (C-7 , C-7 , C-
9
þ
0
00 0 00 0 00 0 00
, C-9 ), 37.1 and 37.1 (C-3 , C-3 , C-5 , C-5 ), 37.9 (C-10 , C-10 ),
C
9
0
00
51.3 (C-4, C-9) 56.4 (C-5, C-10), 60.2 (C-1 , C-1 ), 67.2 (С-3, С-8), 70.8
(
[
С-1, С-6), 82.9 (C-10b, C-10c); MALDI TOF/TOF: m/z (Irel, %): 559
MþK] (40), 543 [MþNa] (30), 519 [MeH] (100). Anal. Calcd. (%)
: С, 73.80; H, 10.06; N, 16.14; found: С, 73.73; H, 10.00;
þ
þ
þ
5
. Biological screening
for C32
52 6
H N
N, 16.10.
5.1. Sample preparation
Samples were provided by the collaborator and stored frozen
4
8
.3.3. 2,7-Bis[1-(1-adamantyl)ethyl]-4,9-dimethyl-2,3
а,5а,7,-
ꢀ
at ꢁ20 C. Samples were prepared in DMSO and water to a final
а
,10 -hexaazaperhydropyrene (17)
а
testing concentration of 32
mg/mL or 20 mM (unless otherwise
Yield 0.32 g (55%), R
54e256 C; nmax (liquid film) 2919e2850 (br), 1451, 1215 cm
f
(CHCl
3
) 0.76, white powdered crystals, mp
о
ꢁ1
indicated in the data sheet), in 384-well, non-binding surface plate
2
; d
H
(
NBS) for each bacterial/fungal strain, and in duplicate (n ¼ 2), and
(
500.17 MHz, CDCl
3
) 0.97 (6H, br. s, CH
, Н-12 ,12 ), 1.42 (6H, d, J 9.2 Hz, CH , Н
,3 ,7 ,7 ,8 ,8 ), 1.55e1.68 (18H, m, CH
3
, Н-11,12), 1.22 and 1.28 (6H,
0
00
keeping the final DMSO concentration to a maximum of 1% DMSO.
All the sample-preparation where done using liquid handling ro-
bots. Compounds that showed solubility issues during stock solu-
tion preparation are detailed in the data sheet.
d, J 5.6 Hz, CH
3
5
3
2
00
а
-
0
0
00
00
0
00
0
00
00
00
0
0
0
00
0
00
0
2
, Н
, H
b
-3 ,3 ,7 ,7 ,8 ,8 ; H-
-5,10), 1.94 (6H, br. s,
0
00
,5 ,10 ,10 ,11 ,11 ), 1.81e1.88 (2H, m, CH
2
а
0
00
0
00
CH, H-4 ,4 ,6 ,6 ,9 ,9 ), 2.25e2.45 (2H, m, CH
2
b
, H -5,10; 6Н, СН,
0
00
Н-1 ,1 ,4,9,10b,10c), 2.98e3.08 (3H, m, CH
1H, m, CH , Н -6), 3.43e3.49 (2H, m, CH , Н
, H -3), 3.89 (1H, d, Jba 8 Hz, CH , H
) 10.3 and 10.8 (C-12 , C-12 ), 16.5 and 16.8 (С-11, C-12), 28.6
2
, Н
а
-1,3,8), 3.16e3.20
2
(
8
2
а
2
b
-1,6), 3.80 (1H, d, Jba
-8); (125.78 MHz,
5.2. Antimicrobial assay
2
Hz, CH
2
b
2
b
d
C
0
00
CDCl
3
5.2.1. Procedure
0
00
0
00
0
00
0
00
0
00
0
(
C-4 , C-4 , C-6 , C-6 , C-9 , C-9 ), 37.4 (C-5 , C-5 , C-10 , C-10 , C-11 ,
All bacteria were cultured in Cation-adjusted Mueller Hinton
0
0
0
00
0
00
0
ꢀ
C-11 ), 38.4 and 38.4 (C-2 , C-2 ), 38.6 and 38.7 (C-3 , C-3 , C-7 , C-
7
6
broth (CAMHB) at 37 C overnight. A sample of each culture was
0
0
0
00
ꢀ
, C-8 , C-8 ), 51.1 and 51.5 (C-4, C-9), 55.7 and 56.3 (C-5, C-10),
then diluted 40-fold in fresh broth and incubated at 37 C for
0
00
6.7 and 67.0 (C-1 , C-1 ), 67.4 and 74.3 (C-3, C-8), 71.2 and 77.3
1.5e3 h. The resultant mid-log phase cultures were diluted (CFU/
(
%
С-1, С-6), 83.1 and 83.3 (C-10b, C-10c); MALDI TOF/TOF: m/z (Irel
,
mL measured by OD600), then added to each well of the compound
þ
þ
þ
): 615 [MþK] (50), 599 [MþNa] (40), 575 [MeH] (100). Anal.
containing plates, giving a cell density of 5
volume of 50
for 18 h without shaking.
ꢂ
105 CFU/mL and a total
ꢀ
Calcd. (%) for C36
H, 10.44; N, 14.51.
60
H N
6
: С, 74.95; H, 10.48; N, 14.57; found: С, 74.89;
mL. All the plates were covered and incubated at 37 C
Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048

E.B. Rakhimova et al. / Tetrahedron xxx (2017) 1e7
7
5
.2.2. Analysis
provided in 4 concentrations, with 2 above and 2 below its MIC
value, and plated into the first 8 wells of column 23 of the 384-well
NBS plates. The quality control (QC) of the assays was determined
Inhibition of bacterial growth was determined measuring
absorbance at 600 nm (OD600), using a Tecan M1000 Pro mono-
chromator plate reader. The percentage of growth inhibition was
calculated for each well, using the negative control (media only)
and positive control (bacteria without inhibitors) on the same plate
as references. The significance of the inhibition values was deter-
mined by modified Z-scores, calculated using the median and MAD
of the samples (no controls) on the same plate. Samples with in-
hibition value above 80% and Z-Score above 2.5 for either replicate
0
by the antimicrobial controls and the Z -factor (using positive and
negative controls). Each plate was deemed to fulfil the quality
0
criteria (pass QC), if the Z -factor was above 0.4, and the antimi-
crobial standards showed full range of activity, with full growth
inhibition at their highest concentration, and no growth inhibition
at their lowest concentration.
(
n ¼ 2 on different plates) were classed as actives. Samples with
Acknowledgments
inhibition values between 50 and 80% and Z-Score above 2.5 for
either replicate (n ¼ 2 on different plates) were classed as partial
actives.
This work was financially supported by the Russian Science
Foundation (Grant RSF N 16-43-02010). The structural studies of
the compounds (3e19) were performed with unique equipment in
ꢀ
5
5
.3. Antifungal assay
"Agidel" collective usage centre. Antimicrobial screening was per-
formed by CO-ADD (The Community for Antimicrobial Drug Dis-
covery), funded by the Wellcome Trust (UK) and The University of
Queensland (Australia).
.3.1. Procedure
Fungi strains were cultured for 3 days on Yeast Extract-Peptone
ꢀ
6
Dextrose (YPD) agar at 30 C. A yeast suspension of 1
1
ꢂ
10 to 5
ꢂ
6
0 CFU/mL (as determined by OD530) was prepared from five
colonies. The suspension was subsequently diluted and added to
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of 50
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10 CFU/mL and a total volume
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7
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Please cite this article in press as: Rakhimova EB, et al., One-pot catalytic synthesis of 2,7-bis-substituted 4,9(10)-dimethyl-2,3a,5a,7,8a,10a-
hexaazaperhydropyrenes, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.10.048