N -Substituted tetrahydropentaazadibenzocycloheptafluorenes-a new type of condensed polyazapolycyclic system

Article abstract of DOI:10.1039/d0nj05270a

The first synthesis of N-substituted tetrahydro-4b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorenes has been successfully accomplished via ring transformation reaction of 1,3,5-tricycloalkyl-1,3,5-triazinanes with octahydro-2,2′-biquinazoline in the presence of NiCl2·6H2O as a catalyst. The structure was established on the basis of spectral data, mainly 1D (1H, 13C) and 2D (HSQC, HMBC, COSY) NMR spectra, and X-ray diffraction data. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. This journal is

Full text of DOI:10.1039/d0nj05270a

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DOI: 10.1039/D0NJ05270A
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N-Substituted Tetrahydropentaazadibenzocycloheptafluorenes –
A New Type of Condensed Polyazapolycyclic System
Received 00th January 20xx,
Accepted 00th January 20xx
Elena B. Rakhimova,* Victor Yu. Kirsanov, Ekaterina S. Mescheryakova, Leonard M. Khalilov,
Askhat G. Ibragimov
DOI: 10.1039/x0xx00000x
The first synthesis of N-substituted tetrahydro-4b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorenes
has been successfully accomplished via ring transformation reaction of 1,3,5-tricycloalkyl-1,3,5-triazinanes with octahydro-
2,2'-biquinazoline in the presence of NiCl
2
·6H
2
O as a catalyst. The structure was established on the basis of spectral data,
mainly 1D ( H, 13C) and 2D (HSQC, HMBC, COSY) NMR spectra, and X-ray diffraction data. Hirshfeld surface analysis was
1
used to study intermolecular interactions in the crystal.
Introduction
Results and discussion
There is a large body of data in the scientific literature on the
development of general methods for the synthesis of tricyclic
fused nitrogen-containing systems derived from fluorene [1].
The interest in azafluorenes is related to the discovery of plant
alkaloids, mainly with the 4-azafluorenone structure, and to
the discovery of various types of biological activity in some
azafluorene derivatives, e.g., antihistaminic [2], neurotropic
In our previous works [23, 24], we have demonstrated that a
one-pot synthesis of N,N'-disubstituted annelated
polyazapolycycles can be realized via a catalytic reaction of
condensed difurazanotetraazadecalin and isolated
biperimidine II with 1,3,5-tricycloalkyl-1,3,5-triazinanes as
cycloaminomethylating reagents. In the present work we
demonstrate for the first time that 1,3,5-triazinane is involved
in sequential reactions of cycloaminomethylation and
cyclomethylation with the formation of N-monosubstituted
tetrahydro-4b,5a,10b,12,13a-
I
[
3], antitumor [4], and antibacterial [5] activities. Methods for
the synthesis [6–10] and antitumor activities [11–13] were
reported for tetracyclic azabenzofluorene derivatives, which
can be arranged in terms of the relative positions of the rings
and the presence of endocyclic nitrogen atoms. Also,
noteworthy is a series of studies [14-19] describing the
pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorenes.
Previos work
R
a)
synthesis
of
disubstituted
perhydro-2,3а,4а,6,7а,8а-
N
H
N
H
N
R
N
hexaazacyclopenta[def]fluorenes, which were found to exhibit
antimicrobial and antitumor [20] properties. In view of the
broad range of pharmacological action of fluorene derivatives
containing azafluorene moiety in the molecule, the synthesis
of new compounds of this class is obviously a promising trend.
Construction of heterocyclic assemblies of said class of
compounds is captivating in terms of creating hybrid
molecules [21, 22]. By combining several pharmacologically
active subunits in the compound structure, formation of a
leader compound can be achieved, which possesses certain
physiological activity and has high affinity for an object of its
action.
N
N
N
N
[Ni]
N
N
N
N
N
N
N
N
O
O
+
R
N
O
O
N
H
N
H
N
R
I
ref [23]
N
R
R
N
b)
R
NH HN
N
N
N
N
N
[Ni]
+
R
N
NH HN
N
R
II
N
R
ref [24]
This work
R
NH HN
NH HN
N
[Ni]
N
N
+ R
N
N
N
N
R
N
R
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
Since our intent was to prepare substituted tetrahydro-
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
def]fluorenes as a new type of a fused polyazapolycyclic
1
41 Prospekt Oktyabrya, 450075 Ufa, Russian Federation
Corresponding author. E-mail: rakhimovaelena@mail.ru
Electronic Supplementary Information (ESI) available: NMR spectra for products, X-
ray data. See DOI: 10.1039/x0xx00000x
4
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system, at the initial stage we have focused on studying tricyclopropyl-1,3,5-triazinane in the presence ofViecwaAtratilcylestOsnli[n5e
condensation of primary amines of various structures (R = mol %] based on transition metal salts anDdOrIa: 1r0e.1e0a3r9t/hD0eNleJ0m5e27n0tAs
alkyl, cycloalkyl, aryl, hetaryl) with formaldehyde and (Table 1).
octahydro-2,2'-biquinazoline (1) [25], which served as initial
building block. It was found that under conditions we used (20
Table 1. Yields of compound 3 in the presence of catalysts.
Catalysts,
5 mol %
Yields,
%
56
52
48
45
42
Catalysts,
5 mol %
Yields,
%
35
34
40
38
29
°
С, MeOH-DMSO), primary amines do not undergo the
condensation reaction, and only cyclomethylation involving
the secondary amino groups of octahydro-2,2'-biquinazoline
NiCl
CoCl
FeCl
PtCl
Cp TiCl
2
×6H
×6H
×6H
2
O
CuCl
PdCl
EuCl ×6H
LaCl ×6H
SmCl ×6H
2
×6H
2
2
O
2
2
O
O
0
1
2
3
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0
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0
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9
0
1
2
3
4
5
6
7
8
9
0
3
2
3
2
O
O
(
1) takes place to give unsubstituted 4b,5a,10b,11a-
tetraazadibenzo[a,h]cyclopenta[def]fluorene (2) in 79% yield
Scheme 1). Dihydrotetraazadibenzocyclopentafluorene (2)
2
3
2
2
2
3
2
O
(
Probably, the tested catalysts behave like Lewis acids [31].
Lewis acid is an electron-pair acceptor and therefore able to
react with a Lewis base to form a Lewis adduct by sharing the
electron pair furnished by the Lewis base [32]. According to
Pearson acid–base concept [33], the strength of adduct
formation is predicted based on two key concepts: (1) “hard
acid–hard base” interactions are stronger than “hard acid–soft
base” or “soft acid–hard base” interactions; (2) “soft acid–soft
base” interactions are stronger than “soft acid–hard base” or
precipitates from the reaction mixture, while the products of
reactions between primary amines and formaldehyde remain
in the mother liquor. Reaction time was 1 hour. The reaction
carried out in both thermal and catalytic variants did not lead
to formation of N,N-disubstituted polyazapolycycle. Instead,
every time we observed formation of exclusively fluorene
derivative 2.
2
NH2
NH2
O
O
H
H
“
hard acid–soft base” interactions. Hard-soft acid–base
+
principle (HSAB) contributes to better understanding of the
mechanism of nucleophilic substitution reactions of transition
metal complexes [34].
0 oC, MeCN
+
2
H , 6 h
The highest yield of product 3 (Scheme 2) was attained
NH HN
NH HN
when the reaction was catalyzed by NiCl
an intermediate acid prefers an intermediate N-donor ligand.
Thus, the interaction of NiCl ·6H O as an intermediate Lewis
2 2
·6H O (56%). Ni (II) as
2
2
octahydro-2,2'-biquinazoline,
acid with triazinane as an intermediate Lewis base leads to the
formation of the most stable acid-base complex.
1
RNH2 + CH O
2
2
NH2
NH2
O
O
H
H
o
X
MeOH-DMSO, 20 C
+
3 R-NH2 + 3 (CH O)n
2
reaction time
R
1
hour
20 oC, MeCN,
0 o
6
C
N
3
1
4
5
+
MeOH, 1h
H , 6 h
4b
a
5a
N
4
6
N
N
N
N
2
N
6a
7
9
R
N
11b
11c
12a
NH HN
NH HN
N
N
8
R
N
12
10a
11a
10b
11
10
N
R
N
R
2
in situ
octahydro-2,2'-biquinazoline
1
Scheme 1. Condensation of octahydro-2,2'-biquinazoline with
primary amines and formaldehyde.
Probably, octahydrobiquinazoline (1) is a highly reactive
and sensitive substrate towards formaldehyde. Therefore, we
assumed the possibility of a one-pot design of substituted
o
MeOH-DMSO, 20 C
X
[Ni]
reaction time
3 hour
R
N
3
4
azafluorene
derivatives
by
heterocyclization
of
5
4b
2
4a
5
a
6
N
N
N
N
octahydrobiquinazoline (1) with 1,3,5-trisubstituted 1,3,5-
triazinanes as efficient cycloaminomethylating reagents [26–
N
13b
N
6a
7
1
14a
13c
8
14
3aN
13
N
1
10a
2
9], which are widely used as organic synthons [30]. According
10b
9
10
N
R
11
N
R
12
to preliminary experiments, the reaction of 1,3,5-
tricyclopropyl-1,3,5-triazinane, formed in situ [26], with
octahydro-2,2'-biquinazoline (1) at 20 С without a catalyst
affords N-cyclopropyl-substituted 4b,5a,10b,12,13a-
pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorene (3) in a
yield not exceeding 10%. We carried out the model reaction
between octahydro-2,2'-biquinazoline (1) and 1,3,5-
3
-8
о
R = cyclo-C H5 (3, 56% yield), cyclo-C H9 (4, 59% yield),
3
5
cyclo-C H (5, 60% yield), cyclo-C H (6, 60% yield),
6
11
7 13
cyclo-C8H15 (7, 63% yield), norbornyl (8, 56% yield)
Scheme 2. Heterocyclization of octahydro-2,2'-biquinazoline
with 1,3,5-tricycloalkyl-1,3,5-triazinanes.
2
| J. Name., 2012, 00, 1-3
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The increase in the catalyst NiCl
mol. % did not induce a significant increase in the yield of the
target heterocycle. The choice of an MeOH-DMSO mixture as
the reaction medium was due to the good solubility of the
starting reactants in this mixture. It is noteworthy that 1,3,5-
tricycloalkyl-1,3,5-triazinanes were obtained without isolation
and were subjected to ring transformation reaction for more
efficient synthesis of the target compounds.
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·6H O concentration to 10
View Article Online
DOI: 10.1039/D0NJ05270A
N
N
+
(CH2O)n
N
N
0 oC,
MeOH, 3 h
R = cycloalkyl
6
3
-8
N
R
R
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-RNH2
-[Ni]
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Under the conditions we used (5 mol. % NiCl
2 2
·6Н О, 20 °С,
3
h, MeOH-DMSO), heterocyclization of octahydro-2,2'-
[
Ni]
biquinazoline (1) with 1,3,5-tricycloalkyl-1,3,5-triazinanes (R =
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
norbornyl) resulted in the selective formation of N-cycloalkyl-
N
N
R
R
R
R
N
N
H
[Ni]
R
N
N
[Ni]
N
NH
N
substituted
12,13,13b,13c-tetrahydro-6H,11H,14H-
4
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
def]fluorenes (3–8) in 56–63% yields (Scheme 2).
-RNH2
+ biquinazoline
1
Presumably (Scheme 3), recyclization of 1,3,5-tricycloalkyl-
R
H
H
R
1
,3,5-triazinane with octahydro-2,2'-biquinazoline 1 proceeds
N
N
R
in sequential stages including coordination [35] of a nitrogen
atom of triazinane with an ion of the central catalyst atom,
followed with nucleophilic addition of a nitrogen atom of
[Ni]
H
HN
N
NH
NH
N
N
N
N
[Ni]
R
N
N
R
CH2
CH2
N
NH
biquinazoline to
a
carbocation thus formed and
H
R
cycloaminomethylation with the formation of an intermediate
compound A. Thus, one pair of secondary amino groups of
octahydrobiquinazoline can be involved into cycloaddition
reaction with the 1,3,5-tricycloalkyl-1,3,5-triazinane moiety as
a three-atomic synthon [30]. Subsequent coordination of a
nitrogen atom of methanediamine B with an ion of the central
catalyst atom followed with nucleophilic addition of a nitrogen
atom of the intermediate A to a carbocation thus formed
promotes cyclomethylation accompanied with a closure into a
five-membered imidazolidine ring. As a result, mono-N-
R
R
[
Ni]
N
N
R
R
N
H
H
B
N
H
[Ni]
H
N
N
NH
N
N
NH
H C
2
R
N
N
R
NH
- CH2(NHR)2
- [Ni]
NH
A
substituted
tetrahydro-4b,5a,10b,12,13a-
Scheme 3. The possible reaction pathway.
pentaazadibenzo[a,h]-cyclohepta[1,2,3,4-def]fluorenes (3-8)
are exclusively formed.
The structure of 12-cyclopropyl-12,13,13b,13c-tetrahydro-
6
H,11H,14H-4b,5a,10b,12,13a-
pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorene
Tetrahydropentaazadibenzocycloheptafluorenes
were isolated in a pure state, their structure was established
using advanced spectroscopic techniques. The Н NMR spectra
of compounds 3–8 normally exhibit two pairs of doublets of an
АВ spin system at 3.31–4.98 ppm with the geminal spin–spin
coupling constant of 11–13 Hz. These signals correspond to the
(3–8)
(3)
was
1
confirmed by X-ray diffraction data (Fig. 1). Compound 3 forms
prismatic transparent crystals with a monoclinic crystal lattice
space group Р21/n). The independent part of the unit cell
contains one molecule of compound 3 (Z=4, Z’=1). According
(
methylene protons at the carbon atoms located between two to X-ray diffraction data, compound 3 is an annulated polyaza
1
1,13
positions. The NOESY spectra exhibit polycycle with a cyclopropane substituent at the N12 nitrogen
nitrogen atoms in H
cross-peaks for H13 and H protons, which is indicative of their atom. The imidazolidine ring has an envelope conformation, in
14
1
3
13с
spatial proximity. In the С NMR spectra, the formation of the which the С atom deviates from the mean plane through the
pentaazapolycyclic cage of compounds 3–8 is confirmed by
N
5a–C –N4b–C13b atoms by 0.6269(19)Å. It is known [36] that
5
signals in the 63.8–66.6 ppm and 73.3–75.3 ppm ranges, which
the perhydrofluorene molecule is strained, because of
pronounced distortion of the five-membered ring. The 1,3,5-
triazepane ring in 3 has a slightly distorted chair conformation.
The six-membered azacycles exist as identical sofa
conformations, as evidenced by the folding amplitudes, which
coincide within the experimental error (Q = 0.4957(15) Å, Q =
correspond to С1
1,13
carbon atoms. The signals were assigned
on the basis of homo- and heteronuclear 2D NMR
experiments. The proposed structures are confirmed by the
presence of molecular ion peaks in the MALDI TOF/TOF mass
spectra.
0
.4982(14) Å). The imidazolidine and triazepane rings are
trans-coupled, with the Н13с–С13с–С13b–H13b torsion angle being
1
62.86(12)°.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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energy is 2.03 kcal/mol, and the electron density and its
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13b
10.1039/D0NJ05270A
Laplacian at the CP (3,-1) are high. TheDOНI: hydrogen atom
also participates in the С13b–H13b…N5а hydrogen bond. Note
that the strengths of components of the indicated bifurcated
hydrogen bond are markedly different, as indicated by the
N…H interatomic distances. Indeed, the H13b…N10b distance is
2.704Å, whereas the H13b…N5а distance is 2.947Å. The high
ellipticity at the CP (3,-1) of the С13b–H13b…N5а bond indicates
that this contact is forced. The topological analysis of the
electron density of the crystal of 3 indicated that the CP (3,-1)
Figure 1. Molecular structure of compound 3 according to X-
ray diffraction data. Non-hydrogen atoms are shown by
thermal vibration ellipsoids (р=30%).
The cyclopropane substituent at N12 nitrogen occupies an
axial position relative to the mean plane of the
polyazapolycyclic cage, which may be indicative of
stereoelectronic effects (SE). Therefore, we carried out natural
bond orbital (NBO) analysis, which revealed several
stereoelectronic interactions in the molecule of 3. An
interaction with an energy of 15.60 kcal/mol was detected
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
is located at the С13–Н13a…N5a bond, with the length of this
bond being greater than the sum of the van der Waals radii by
0
.224Å. In the crystal, the dimers are connected by short
6
a
9
H …H contacts with an energy of 1.5 kcal/mol.
10b
between the lone pair (LP) of the N
atom and the
11
12
antibonding sigma orbital (σ*) of the С –N bond. In the
same N10b–C –N
11
12
moiety, a weaker interaction (3.76
kcal/mol) occurs between the N12 atom LP and the σ* orbital
of the N10b–C11 bond. Similar SE are also inherent in the N13a
–
1
3
12
C –N moiety of the 1,3,5-triazepane ring. The most
pronounced stereoelectronic effects are found in the N10b–
C10a–C10 and N –C –C moieties; this results in more planar
configurations of the N10b and N4b atoms compared with other
nitrogen atoms. The LPs of N5a and N13a atoms also participate
in the stereoelectronic interactions with the σ* orbitals of the
N–C bonds, but the binding energy does not exceed 6
kcal/mol, which apparently accounts for the pyramidal
configurations of these atoms (∑∠N5a=330.39°, ∑∠N13a=326.19°).
It is noteworthy that the conclusions drawn from NBO
analysis are supported also by the results of topological
analysis of electron density in terms of the Bader's theory of
atoms in molecules [37]. Among the C–N bonds, the highest
electron density values (휌(푟)) were found at the critical points
4b
4a
14a
Figure 2. Dimer formed via С–Н…N hydrogen bonds (а),
fragment of the crystal packing along the а axis with indicated
Н…Н contacts (b), Hirshfeld surface with mapped electrostatic
potential (ESP) in the range from -0.065 au (red) through 0.0
(white) to 0.029 au (blue) (с), 2D diagrams with reflected N…Н
bonds (d).
Conclusions
CP) (3,-1) of the N –C , N10b–C10a, N –C , and N –C
12 13 Thus, we demonstrated for the first time that the NiCl
4b
4a
12
11
2 2
·6H O-
(
catalyzed heterocyclization of octahydro-2,2'-biquinazoline
with 1,3,5-tricycloalkyl-1,3,5-triazinanes is an efficient
synthetic route to N-cycloalkyl-substituted 12,13,13b,13c-
tetrahydro-6H,11H,14H-4b,5a,10b,12,13a-
pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorenes, which
represent a conceptually new type of fused polyaza-polycyclic
system. This approach implies the annulation in which a
cycloaminomethylating/cyclomethylating group adds to an
existing cyclic system, which acts the starting building block;
this allows the synthesis of fused systems combining several
types of heterocyclic rings in the molecule in one preparative
bonds, which attests to withdrawal of the electron density to
adjacent bonds due to interaction between nitrogen LPs and
orbitals of these bonds. These interactions result in a
considerable decrease in the N –C , N10b–C10a, N –C , and
4b
4a
12
11
1
2
13
N –C bond lengths with respect to the standard values
1
2
11
10b
12
11
(
1.47Å). For example, in the N –C –N moiety, the N –C
bond length is 1.427 Å (휌(푟) = 0.2906 e/au3), while the N10b–
1
1
C bond length is 1.466 Å (휌(푟) = 0.2624 e/au3).
In the crystals, the molecules of compound 3 form dimers
0D motif) via the С –H13b…N10b hydrogen bonds (Fig. 2). On
1
3
(
the Hirshfeld surface with mapped electrostatic potentials, step. Synthesis of hybrids comprising structures with
these bonds are represented by interacting electropositive pronounced biological activity and polycyclic ones for
region around the Н13b hydrogen atom (0.015 au) and producing up-to-date pharmaceuticals is of undoubted
electronegative region around the nitrogen atom (-0.043 au). interest. Our future strategy includes expanding the range of
The contribution of the С–Н…N hydrogen bonds to the amino substrates and gaining further insights into the
antimicrobial and antitumor activity of synthesized mono-N-
substituted tetrahydropentaazadibenzocycloheptafluorene
compounds in vitro.
Hirshfeld surface is 6.5%, which is reflected in the two-
dimensional plot as broad spikes. The С13b–H13b…N10b bond
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 5 of 8
Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
recrystallized from CHCl
3
). The final products 3–8 were
Experimental section
View Article Online
DOI: 10.1039/D0NJ05270A
identified by spectroscopic methods.
1
4
The NMR spectra, including two-dimensional homo- (COSY,
NOESY) and heteronuclear (HSQC, HMBC) spectra, were
recorded on a Bruker Avance 500 spectrometer at 500.17 MHz
2-Сyclopropyl-12,13,13b,13c-tetrahydro-6H,11H,14H-
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
def]fluorene (3). Light yellow crystals; yield 0.20 g (56%); mp
1
13
for H and 125.78 MHz for C according to standard Bruker
procedures. CDCl was used as the solvent, and
о
1
1
0
3
6
50–152 С; R
f 3
0.50 (MeOH). H NMR (500.17 MHz, СDCl ): δ =
3
.51–0.64 m (4H, CH
2
, H-2´,3´), 2.45–2.49 m (1H, CH, H-1´),
tetramethylsilane, as the internal standard. The MALDI
TOF/TOF mass spectra (positive ion detection, sinapic acid
matrix) were obtained on a Bruker AutoflexTM III Smartbeam
mass spectrometer. Samples were prepared by the dried drop
technique. Solutions of a matrix and analyte were mixed at a
ratio of 50: 1 to 100: 1, and a drop of the 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 solid
state UV laser (λ 355 nm). The elemental analyses were
obtained on a Carlo Erba 1106 analyzer. The melting points
were determined on a PHMK 80/2617 melting point
apparatus. All reagents used in the work were purchased from
Sigma-Aldrich and Acros Organics.
2
.42 t (2H, CH
; Jba = 13.5 Hz), 3.88 d (1H, CH
2
, H
a
-6, H
a
-11; Jab = 12.5 Hz), 3.74 d (1H, CH
2 b
, H -
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
, H
a
-14; Jab = 13 Hz), 4.03 d
-5; Jab = 4 Hz), 4.07 d (1H, CH, H-13c; J = 7 Hz),
2
3
(1H, CH
2
, H
a
2
4
1
.11 d (1H, CH
2
, H
b
-14; Jba = 13 Hz), 4.22–4.24 m (1H, CH, H-
2
3b; 1H, CH
2
, H
b
-11), 4.50 d (1H, CH
2
, H
a
-13; Jab = 13 Hz), 4.80
d (1H, CH
2
, H
b
-13; 2Jba = 13 Hz), 4.87 d (1H, CH
2
, H
b
-5; Jba = 4
2
3
3
Hz), 6.44 d (1H, CH, H-4; J = 8 Hz), 6.66 d (1H, CH, H-10, J =
3
8
1
.5 Hz), 6.70 t (2H, CH, H-2,8; J = 7.5 Hz), 7.04 d (2H, CH, H-
3
3
13
,7; J = 7 Hz), 7.16 t (2H, CH, H-3,9; J = 8 Hz). C NMR (125.78
): δ = 8.3 and 8.8 (С-2´,3´), 32.8 (С-1´), 51.3 (C-6),
2.1 (C-14), 66.6 (C-13), 70.0 (C-5), 75.3 (C-11), 80.1 (C-13b),
MHz, CDCl
3
5
8
6
(
(
0.9 (C-13c), 110.0 (C-4,10), 116.5 (C-2), 116.7 (C-8), 119.1 (C-
a,14a), 126.4 (C-7), 127.1 (C-1), 128.0 (C-9), 128.2 (C-3),141.0
+
С-4a), 142.6 (С-10a). MALDI TOF/TOF, m/z: (%) = 358 [M–H]
100). Anal. Calcd. for C22
Heterocyclization
biquinazoline with formaldehyde. A round-bottomed flask
equipped with a magnetic stirrer bar was charged with MeOH
of
1,1',2,2',3,3',4,4'-octahydro-2,2'-
H
25
N
5
: С 73.51; H 7.01; N 19.48.
Found: С 73.39; H 6.96; N 19.41.
Crystal data for 3. C22 , M = 359.47, monoclinic, space
25 5
H N
(5 mL), 2 mmol (0.2 mL) of 37% aqueous formaldehyde
group P2
1
/n, a = 9.5806(4), b = 18.4584(9) and c = 10.4334(4)
solution, 1.00 mmol (0.27 g) octahydro-2,2'-biquinazoline,
prepared by the reported procedure [25], in DMSO (5 mL). The
mixture was stirred at 20 °C for 1 h. The white precipitate was
filtered and washed twice with MeOH (5 mL). The final product
3
Å, α = 90°, β = 91.070(4)°, γ = 90°, V = 1844.74(14) Å , Z = 4,
–3
–1
d
8
0
0
0
calc = 1.294 g·cm , F(000) = 768.0, µ = 0.079 mm . Total of
627 were collected (4221 independent reflections, Rint
.0219) and used in the refinement, which converged to wR
.1079, GOOF 1.019 for all independent reflections [R
.0479 was calculated for 4221 reflections with I ˃ 2σ(I)]. X-ray
=
2
2
1
was identified by spectroscopic methods.
1b,11c-Dihydro-6H,12H-4b,5a,10b,11a-
1
=
tetraazadibenzo[a,h]cyclopenta[def]fluorene
(2).
White
diffraction data were collected on a Agilent XCalibur (Eos,
Gemini) diffractometer with graphite monochromated Mo-Kα
radiation (λ = 0.71073 Å) at 293 K. Collection and processing of
data was performed with using the program CrysAlisPro
Oxford Diffraction Ltd [38]. The structure 3 was solved with the
ShelXS [39] structure solution program using Direct Methods
and refined with the ShelXL [40] refinement package using
Least Squares minimisation. The structure was refined by a
full-matrix least-square technique using anisotropic thermal
parameters for non-hydrogen atoms. The hydrogen atoms
were positioned geometrically and treated using a riding
model, fixing the bond lengths at 0.970, 0.980 and 0.930 Å for
о
powder; yield 0.23 g (79%); mp 170–172 С; R
f
0.55 (MeOH).
1
2
H NMR (500.17 MHz, СDCl
3
): δ = 3.55 d (2H, CH
-6,12; Jab = 17 Hz), 4.51 d (2H, CH
2
, H
a
-5,11; Jab
2
=
H
3 Hz), 3.91 d (2H, CH
2
, H
a
2
,
2
2
b
-6,12; Jba = 17 Hz), 4.72 d (2H, CH
2
, H
b
-5,11; Jba = 3 Hz), 5.13
3
br.s (2H, CH, H-11b,11c), 6.47 d (2H, CH, H-4,10; J = 8 Hz), 6.75
t (2H, CH, H-2,8; J = 7.5 Hz), 6.97 d (2H, CH, H-1,7; J = 7.5 Hz),
3
3
3
13
7
.07 t (2H, CH, H-3,9; J = 8 Hz). C NMR (125.78 MHz, CDCl
3
):
δ = 46.7 (C-6,12), 70.8 (C-5,11), 77.7 (C-11b,11c), 114.7 (C-
4
3
,10), 117.0 (C-6a,12a), 118.6 (C-2,10), 127.2 (C-1,7), 128.0 (C-
,9), 142.1 (С-4a,10a). MALDI TOF/TOF, m/z: (%) = 289 [M–H]
+
(100). Anal. Calcd. for C18
18 4
H N : С 74.46; H 6.24; N 19.30.
Found: С 74.37; H 6.21; N 19.20.
2
CH , CH and CHar atoms, respectively. CCDC 1990121 contains
Heterocyclization of octahydro-2,2'-biquinazoline with 1,3,5-
trisubstituted 1,3,5-triazinanes, prepared in situ from
paraformaldehyde and cycloalkylamines (general procedure).
A round-bottomed flask equipped with a magnetic stirrer bar
was charged with MeOH (10 mL), the appropriate
cycloalkylamine (3.00 mmol), paraformaldehyde (0.09 g, 3.00
mmol), and the mixture was stirred at 60 °C for 1 h. Then the
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
2-Сyclopenthyl-12,13,13b,13c-tetrahydro-6H,11H,14H-
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
1
4
def]fluorene (4). Light yellow powder; yield 0.23 g (59%); mp
о
1
1
1
3
CH
H
48–150 С; R
.40–1.44 m (2H, CH
´,4´), 1.70–1.77 m (3H, CH
, H -5´), 3.31–3.37 m (1H, CH, H-1´), 3.40 d (2H, CH
f
0.55 (MeOH). H NMR (500.17 MHz, СDCl
, H -2´,5´), 1.52–1.58 m (2H, CH
, H -2´,3´,4´), 2.00–2.05 m (1H,
, H -6,
3
): δ =
reaction mixture was cooled to a temperature of ~20 °C,
2
a
2 a
, H -
.
NiCl
2
2
6H O (0.012 g, 0.05 mmol), octahydro-2,2'-biquinazoline
2
b
(0.27 g, 1.00 mmol) in DMSO (5 mL) were added, and the
2
b
2
a
mixture was stirred at 20 °C for 3 h. The precipitates that
formed were filtered off and washed with methanol (2 × 10
mL) to obtain pure compounds 3–8 as light yellow powders
2
2
a
-11; Jab = 13 Hz), 3.68 d (1H, CH
2
, H
b
-6; Jba = 14 Hz), 3.85 d
2
2
(1H, CH
2 a
, H -14; Jab = 13 Hz), 3.95 d (1H, CH
2
, H
a
-5; Jab = 3.5
2 b
Hz), 4.07 br.s (2H, CH, H-13b,13c), 4.09 br.s (1H, CH , H -14),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Page 6 of 8
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
J
.31 d (1H, CH
ab = 13 Hz), 4.87 d (1H, CH
2
, H
b
-11; 2Jba = 12.5 Hz), 4.48 d (1H, CH
2
, H
a
-13; Calcd. for C26
H
33
N
5
: С 75.14; H 8.01; N 16.85. Found: С 75.03; H
View Article Online
2
2
DOI: 10.1039/D0NJ05270A
2
, H
b
-5; Jba = 3.5 Hz), 4.98 d (1H, 7.95; N 16.74.
2
3
CH
2 b
, H -13; Jba = 13 Hz), 6.43 d (1H, CH, H-4; J = 8 Hz), 6.63– 12-Сyclooctyl-12,13,13b,13c-tetrahydro-6H,11H,14H-
6
7
.70 m (3H, CH, H-2,8,10), 7.00–7.04 m (2H, CH, H-1,7), 7.13– 4b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
.17 m (2H, CH, H-3,9). C NMR (125.78 MHz, CDCl ): δ = 22.9 def]fluorene (7). Light yellow powder; yield 0.27 g (63%); mp
3
1
3
о
1
and 23.1 (С-3´,4´), 31.2 and 31.7 (С-2´,5´), 51.1 (C-6); 52.4 (C- 154–156 С; R
f
0.60 (MeOH). H NMR (500.17 MHz, СDCl
3
): δ =
1
1
4), 60.1 (С-1´), 65.2 (C-13), 69.9 (C-5), 75.2 (C-11), 80.5 (C- 1.45–1.60 m (8H, CH , H -4´,6´; H-3´,5´,7´), 1.69 br.s (4H, CH ,
3b), 80.7 (C-13c), 109.7 (C-4), 109.9 (C-10), 116.3 (C-2), 116.6
2
a
2
a b
H -2´,8´; H -4´,6´), 1.91 br.s (2H, CH
2
, H
b
-2´,8´), 3.14 br.s (1H,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(C-8), 118.7 (C-14a), 119.1 (C-6a), 126.3 (C-7), 127.3 (C-1), CH, H-1´), 3.32 d (1H, CH
2
, H
a
-11; Jab = 11 Hz), 3.39 d (1H, CH
2
,
2
2
1
28.1 (C-3,9), 141.0 (С-4a), 142.3 (С-10a). MALDI TOF/TOF,
H
a
-6; Jab = 12 Hz), 3.67 d (1H, CH
2
, H
b
-6; Jba = 12.5 Hz), 3.84 d
-14; Jab = 12 Hz), 3.98 br.s (1H, CH, H-13c), 4.04
+
2
m/z: (%) = 386 [M–H] (50). Anal. Calcd. for C24
H 7.55; N 18.07. Found: С 74.29; H 7.50; N 17.96.
H
29
N
5
: С 74.38; (1H, CH
br.s (2H, CH
(1H, CH , H
Hz), 4.80 br.s (1H, CH
2
, H
a
2
, H
a
2
-5; H
b
-14), 4.21 br.s (1H, CH, H-13b), 4.32 d
2
1
4
2-Сyclohexyl-12,13,13b,13c-tetrahydro-6H,11H,14H-
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
2
b
-11; Jba = 11 Hz), 4.44 d (1H, CH
2
, H
a
-13; Jab = 11.5
-13; 2Jba = 12
2
, H -5), 4.91 d (1H, CH
b
2
, H
b
def]fluorene (5). Light yellow powder; yield 0.24 g (60%); mp Hz), 6.44 br.s (1H, CH, H-10), 6.62 br.s (1H, CH, H-4), 6.69 br.s
о
1
1
1
H
51–153 С; R
.17–1.25 m (5H, CH
-4´), 1.68–1.71 m (2H, CH
f
0.60 (MeOH). H NMR (500.17 MHz, СDCl
, H -2´,3´,4´,5´,6´), 1.57–1.62 m (1H, CH
b
, H -3´,5´), 1.85 br.s (1H, CH , H -
3
): δ = (2H, CH, H-2,8), 7.02 br.s (2H, CH, H-1,7), 7.15 br.s (2H, CH, H-
1
3
2
a
2
,
3,9). C NMR (125.78 MHz, CDCl
3
): δ = 23.2 and 23.3 (С-4´,6´),
25.2 (С-5´), 27.6 and 27.7 (С-3´,7´), 28.8 and 28.9 (С-2´,8´), 51.2
-6´), 2.92 br.s (1H, CH, H-1´), 3.32 d (C-6), 52.0 (C-14), 58.6 (С-1´), 65.4 (C-13), 69.8 (C-5), 74.5 (C-
b
2
b
2
2
´), 2.11 br.s (1H, CH
2
, H
b
2
2
(1H, CH
2
, H
a
-11; Jab = 12.5 Hz), 3.39 d (1H, CH
2
, H
a
-6; Jab = 13 11), 79.7 (C-13b), 81.0 (C-13c), 109.7 (C-4), 110.0 (C-10), 116.2
2
Hz), 3.67 d (1H, CH
2
, H
b
-6; Jba = 14 Hz), 3.84 d (1H, CH
2
, H
a
-14; (C-2), 116.5 (C-8), 119.1 (C-14a), 119.6 (C-6a), 126.4 (C-7),
-5), 4.06 127.1 (C-1), 128.1 (C-3,9), 141.2 (С-4a), 142.1 (С-10a). MALDI
-14; Jba = 13 Hz), 4.12 d (1H, CH, H-13b; J = 6.5 TOF/TOF, m/z: (%) = 428 [M–H] (100). Anal. Calcd. for
2
Jab = 13.5 Hz), 3.95–4.01 m (1H, CH, H-13c; 1H, CH
2
, H
a
2
3
+
d (1H, CH
Hz), 4.41 t (2H, CH
2
, H
b
2
2
, H
b
-11, H
, H
a
-13; J = 13 Hz), 4.82 br.s (1H,
27 35 5
C H N : С 75.49; H 8.21; N 16.30. Found: С 75.35; H 8.17; N
CH , H -5), 4.97 d (1H, CH
2
b
2
b
-13; 2Jba = 13 Hz), 6.43 d (1H, CH, 16.22.
3
3
H-10; J = 7.5 Hz), 6.61 d (1H, CH, H-4; J = 8 Hz), 6.65–6.71 m 12-Dibicyclo[2.2.1]hept-2-yl-12,13,13b,13c-tetrahydro-
(
2H, CH, H-2,8), 7.00–7.04 m (2H, CH, H-1,7), 7.15 d (2H, CH, H- 6H,11H,14H-4b,5a,10b,12,13a-
,9; J = 7.5 Hz). C NMR (125.78 MHz, CDCl
5.3 (С-3´,5´), 25.9 (С-4´), 31.1 and 31.4 (С-2´,6´), 51.1 (C-6), Light yellow powder; yield 0.23 g (56%); mp 155–157 С; R
2.0 (C-14), 56.8 (С-1´), 64.2 (C-13), 69.7 (C-5), 73.6 (C-11), 0.55 (MeOH). H NMR (500.17 MHz, СDCl
9.9 (C-13b), 81.1 (C-13c), 109.8 (C-4), 110.0 (C-10), 116.2 (C- (1H, CH
), 116.5 (C-8), 119.0 (C-14a), 119.5 (C-6a), 126.4 (C-7), 127.1
3
13
3
2
5
7
2
3
): δ = 25.0 and pentaazadibenzo[a,h]cyclohepta[1,2,3,4-def]fluorene
(8).
о
f
1
3
): δ = 0.95–0.98 m
-7´), 1.16 d (1H, CH ,
2
-5´; H -3´,6´,7´),
a b
-5´), 2.10 br.s (1H, CH, H-2´), 2.26 br.s
2
, H
a
-6´), 1.02–1.07 m (1H, CH
2
, H
a
3
H
a
-3´; J = 9.5 Hz), 1.41–1.47 m (4H, CH
2
, H
(C-1), 128.1 (C-9), 128.1 (C-3), 141.1 (С-4a), 142.1 (С-10a). 1.58–1.62 m (1H, CH
2
, H
b
+
MALDI TOF/TOF, m/z: (%) = 400 [M–H] (50). Anal. Calcd. for (1H, CH, H-4´), 2.88 br.s and 3.13 br.s (1H, CH, H-1´), 3.31 t (1H,
2
2
C
1
1
4
25
H
7.35.
31
N
5
: С 74.78; H 7.78; N 17.44. Found: С 74.67; H 7.72; N CH
2
, H
a
-11; Jab = 12.5 Hz), 3.40 t (1H, CH
2
, H
a
-6; Jab = 14.5 Hz),
, H
-14),
2
3.68 t (1H, CH
14), 3.95–4.07 m (2H, CH, H-13b,13c; 2H, CH
4.20 d (1H, CH
2
, H
b
-6; Jba = 14.5 Hz), 3.82–3.86 m (1H, CH
2
a
-
2-Сycloheptyl-12,13,13b,13c-tetrahydro-6H,11H,14H-
b,5a,10b,12,13a-pentaazadibenzo[a,h]cyclohepta[1,2,3,4-
2
, H
a
-5; H
b
2
2
, H
b
-11; Jba = 12.5 Hz), 4.34–4.40 m (1H, CH
2
,
2
def]fluorene (6). Light yellow powder; yield 0.25 g (60%); mp
a
H -13), 4.83–4.87 m (1H, CH
2
, H
b
3
-5), 4.95 d (1H, CH
2 b
, H -13; Jba
о
1
1
1
H
52–154 С; R
.35–1.40 m (2H, CH
-3´,6´; H-4´,5´), 1.75–1.82 m (1H, CH
f
0.60 (MeOH). H NMR (500.17 MHz, СDCl
, H -3´,6´), 1.50–1.65 m (8H, CH , H
, H -2´), 1.95–1.99 m H-3,9). C NMR (125.78 MHz, CDCl
3
): δ = = 13.5 Hz), 6.43 d (1H, CH, H-4; J = 8 Hz), 6.62–6.69 m (3H, CH,
-2´,7´; H-2,8,10), 7.01–7.03 m (2H, CH, H-1,7), 7.12–7.18 m (2H, CH,
): δ = 27.4 (С-6´), 28.7 (С-
7´), 35.3 and 35.4 (С-3´), 35.6 and 35.9 (С-4´), 38.1 and 38.3 (С-
-6; Jab = 14 Hz), 3.68 d 2´), 39.2 and 39.9 (С-5´), 50.9 and 51.2 (C-6), 52.0 and 52.4 (C-
2
a
2
a
1
3
b
2
b
3
(
H
1H, CH
2
, H
b
-7´), 3.10–3.15 m (1H, CH, H-1´), 3.32 d (1H, CH
2
,
2
2
a
-11; Jab = 12.5 Hz), 3.40 d (1H, CH
2
, H
a
2
2
(1H, CH
2
, H
b
-6; Jba = 14 Hz), 3.85 d (1H, CH
2
, H
a
-14; Jab = 13.5 14), 60.6 and 60.9 (С-1´), 63.8 (C-13), 69.5 and 70.0 (C-5), 73.3
3
Hz), 3.95 d (1H, CH, H-13c; J = 7 Hz), 4.05–4.08 m (2H, CH
2
, H
a
-
-
and 73.5 (C-11), 80.1 and 80.5 (C-13b), 81.1 (C-13c), 109.7 and
109.8 (C-4), 109.9 (C-10), 116.3 and 116.4 (C-2), 116.5 and
-13; Jab = 13 Hz), 4.79 d 116.6 (C-8), 118.8 and 118.9 (C-14a), 119.3 (C-6a), 126.3 and
3
5
1
; H
b
2
-14), 4.24 d (1H, CH, H-13b; J = 7 Hz), 4.31 d (1H, CH
2
, H
b
2
1; Jba = 12.5 Hz), 4.44 d (1H, CH
2
, H
a
2
2
(1H, CH
2
, H
b
-5; Jba = 4.5 Hz), 4.90 d (1H, CH
2
, H
b
-13; Jba = 13 126.4 (C-7), 127.1 and 127.2 (C-1), 128.0 and 128.1 (C-9), 128.1
3
3
Hz), 6.44 d (1H, CH, H-10; J = 8 Hz), 6.60 d (1H, CH, H-4; J = 8 and 128.2 (C-3), 141.1 (С-4a), 142.0 and 142.7 (С-10a). MALDI
Hz), 6.65–6.70 m (2H, CH, H-2,8), 7.00–7.05 m (2H, CH, H-1,7), TOF/TOF, m/z: (%) = 412 [M–H] (100). Anal. Calcd. for
+
1
3
7
2
5
.12–7.17 m (2H, CH, H-3,9). C NMR (125.78 MHz, CDCl
3.9 and 24.0 (С-3´,6´), 28.0 (С-4´,5´), 32.7 and 32.9 (С-2´,7´), 16.82.
1.2 (C-6), 51.9 (C-14), 60.2 (С-1´), 65.4 (C-13), 69.8 (C-5), 74.6
3
): δ =
26 31 5
C H N : С 75.51; H 7.56; N 16.93. Found: С 75.40; H 7.51; N
(C-11), 79.4 (C-13b), 81.1 (C-13c), 109.8 (C-4), 110.1 (C-10),
Conflicts of interest
There are no conflicts of interest to declare.
1
7
16.3 (C-2), 116.5 (C-8), 119.2 (C-14a), 119.6 (C-6a), 126.4 (C-
), 127.0 (C-1), 128.0 (C-3,9), 141.2 (С-4a), 142.2 (С-10a). Anal.
6
| J. Name., 2012, 00, 1-3
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Ple Na es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
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Acknowledgements
Commun., 2007, 17, 321.
DOI: 10.1039/D0NJ05270A
This research has been supported by the Scholarships of the
President of the Russian Federation for young scientists and
graduate students (SP-197.2019.4) and has been carried out in
accordance with the approved plans for research projects at
the Institute of Petrochemistry and Catalysis of the Russian
Academy of Sciences (RAS) on the topic titled "Metal complex
and heterogeneous catalysis in the design of
macroheterocycles and heteroatomic compounds". State
Registration No. AAAA-A19-119022290010-9 (2019-2021). The
structural studies of synthesized compounds (2–8) were
carried out at the “Agidel” Center for Collective Use at the Ufa
Federal Research Center of the Russian Academy of Sciences
with the financial support of the Russian Ministry of Education
and Science (Grant 2019-05-595-000-058).
9 R. R. Khairullina, A. R. Geniyatova, E. S. Meshcheryakova, L.
M. Khalilov, A. G. Ibragimov, U. M. Dzhemilev, Russ. J. Org.
Chem., 2015, 51, 116.
20 Ya. A. Barsegyan, V. V. Baranov, A. N. Kravchenko, Yu. A.
Strelenko, L. V. Anikina, V. A. Karnoukhova, N. G. Kolotyrkina,
Synthesis, 2018, 50, 2099.
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1 B. Meunier, Acc. Chem. Res., 2008, 41, 1, 69.
2 Shaveta, S. Mishra, P. Singh, Eur. J. Med. Chem., 2016, 124,
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9, 500.
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3 E. B. Rakhimova, V. Yu. Kirsanov, E. S. Mescheryakova, L. M.
Khalilov, A. G. Ibragimov, L. U. Dzhemileva, V. A. D’yakonov,
U. M. Dzhemilev, ACS Med. Chem. Lett., 2019, 10, 378.
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New Journal of Chemistry
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NH HN
NH HN
N
N
View Article Online
DOI: 10.1039/D0NJ05270A
[Ni]
N
N
+
R
N
R
N
N
R N
6 examples, 56-63% yield
chromatography free
R
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Ni-Catalyzed heterocyclization of octahydro-2,2'-biquinazoline with 1,3,5-triazinanes is an efficient
synthetic route to mono-N-substituted tetrahydro-4b,5a,10b,12,13a-pentaazadibenzo[a,h]-
cyclohepta[1,2,3,4-def]fluorenes.