Reactions of octahydroacridine-4-carbonitrile (carboxamide) with electrophilic reagents

Article abstract of DOI:10.1007/s10593-015-1703-8

[MediaObject not available: see fulltext.]Octahydroacridine-4-carbonitrile (carboxamide) was shown to react with aryldiazonium salts and other electrophilic reagents in acidic and neutral media. The reactions occurred at the methine carbon atom, forming the corresponding 4-functionalized derivatives. The obtained azo compounds decomposed at 140-155°C with elimination of nitrogen and gave products formed by the reactions of radical intermediates.

Full text of DOI:10.1007/s10593-015-1703-8

DOI 10.1007/s10593-015-1703-8
Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
Reactions of octahydroacridine-4-carbonitrile
(carboxamide) with electrophilic reagents
Ekaterina V. Zaliznaya1, Oleg K. Farat1*, Nikolay Yu. Gorobets2, Viktor I. Markov1,
Roman I. Zubatyuk2, Aleksandr V. Mazepa3, Elena V. Vashchenko2
1 Ukrainian State University of Chemical Technology,
8 Gagarina Ave., Dnepropetrovsk 49005, Ukraine; е-mail: faratok@mail.ru
2 State Scientific Institution "Institute for Single Crystals", National Academy of Sciences of Ukraine,
60 Lenina Ave, Kharkiv 61001, Ukraine; е-mail: nikolay.gorobets@gmail.com
3 A. V. Bogatskii Physicochemical Institute, National Academy of Sciences of Ukraine,
86 Lyustdorfskaya Road, Odessa 65080, Ukraine; е-mail: almazepa@rambler.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(4), 327–333
Submitted February 10, 2015
Accepted after revision April 3, 2015
O
X = CN, E = N2Ar, Cl, NO2,
X = CONH2, E = N2Ar, NO2
N
N
N
Ph
X
E
O
X
Octahydroacridine-4-carbonitrile (carboxamide) was shown to react with aryldiazonium salts and other electrophilic reagents in acidic
and neutral media. The reactions occurred at the methine carbon atom, forming the corresponding 4-functionalized derivatives. The
obtained azo compounds decomposed at 140–155°С with elimination of nitrogen and gave products formed by the reactions of radical
intermediates.
Keywords: diazonium salt, octahydroacridines, azo coupling, electrophilic substitution, Japp–Klingemann reaction, radical, radical
reactions.
We have previously described a nontrivial transformation
salts obtained from toluidine and aniline can also
participate in azo coupling reactions. Prior to our work
there were three examples of similar transformations
described in the literature, namely, interaction of 1,2,3,4-
tetrahydroacridine-4-carbonitrile and 2,3-dihydro-1H-cyclo-
penta[b]quinoline-3-carbonitrile with diazonium salts.3 In the
current work we established that this reaction is generally
applicable, and the nature of substituents in the aryl ring of
diazonium salts can be varied widely, producing azo
coupling products 4a–h in 40–70% yields (Scheme 2).
We should note that compounds 4a–h are easily isolated
from the reaction medium and do not require additional
purification. Also, unlike the standard azo coupling
conditions in alkaline medium, the reaction in the case of
octahydroacridine 2 occurred easily in acidic medium. In
our opinion, this can be explained by tautomerism of
substrate 2, resulting in the generation of nucleophilic
enamine center, susceptible to electrophilic attack by
diazonium salt (Scheme 3).
of
5',6',7',8'-tetrahydro-1'H-spiro[cyclohexane-1,2'-quin-
azolin]-4'(3'H)-one (1) to hydroacridine derivatives 2 and 3
that formed under Vilsmeier–Haack reaction conditions
(Scheme 1).1 1,2,3,4,5,6,7,8-Octahydroacridine-4-carbo-
nitrile (2) was easily isolated from the reaction product
mixture by extraction with methanol, providing a relatively
easy access to this compound.
Preliminary study of the chemical properties of nitrile 2
showed that it reacted quite readily in azo coupling with
diazonium salts containing an activating nitro group.2
Further investigation showed that unactivated diazonium
Scheme 1
H
N
POCl3
NH
DMF, rt, 5 days
CN
O
1
+
As known from the literature,4 coupling reaction with
diazonium salts leading to the formation of arylhydrazones in
the presence of a large excess of base in ethanol can also be
achieved with (4-nitrophenyl)acetonitrile, while alternative
N
N
H
CN
CHO
CHO
2 (42%)
3 (10%)
0009-3122/15/5104-0327©2015 Springer Science+Business Media New York
327

Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
4 a R1 = R2 = H, R3 = NO2 (55%);
Scheme 2
b R1 = R3 = H, R2 = NO2 (65%);
c R1 = NO2, R2 = R3 = H (61%);
d R1 = Me, R2 = H, R3 = NO2 (70%);
e R1 = NO2, R2 = H, R3 = Me (70%);
f R1 = R2 = H, R3 = SO2NH2 (65%);
g R1 = R2 = R3 = H (40%);
N2+
X
R1
NH2
NaNO2, AcOH
H2SO4 or HCl
R1
R2
N
2, AcOH
NC N N
R1
R3
0°C – rt
15 min
R2
0°C, 10 min
R2
R3
R3
4a–h
h R1 = R2 = H, R3 = Me (42%)
X– = HSO4– (for 4a–f), X– = Cl– (for 4g,h)
Scheme 3
N
N
H
CN
CN
2
routes were employed for the preparation of hydrazones
from benzyl cyanide.4–8 Comparing the conditions and
results of these reactions with azo coupling of compounds 2,
we can conclude that the pyridine ring in the structure of
compound 2 substantially facilitates azo coupling reactions.
Amide 5, readily available by acidic hydrolysis of nitrile
2,2 also participated in azo coupling reaction, which
occurred analogously in acetic acid (Scheme 4).
A reaction of diazonium salts with β-dicarbonyl
compounds in the presence of bases (Japp–Klingemann
reaction) is known in the literature.9 Elimination of one
carbonyl group usually occurs under these conditions and
hydrazones are formed instead of azo compounds. In our
case, in a mixture of acetic, nitrous, and hydrochloric acids,
elimination of the amide group did not occur, but azo
compounds 6а,b were formed instead (Scheme 4).
Figure 1. The structure of compound 4с represented as non-
hydrogen atoms by thermal vibration ellipsoids of 50%
probability.
–0.23, 0.49, –0.30, and 0.45 Å, respectively. The nitrile
substituent was oriented axially relative to the partially
saturated ring (the torsion angle С(8)–С(13)–С(12)–С(14)
was –101.55(17)°). The nitro group was only slightly
rotated relative to the benzene ring (the torsion angle
N(5)–C(16)–C(17)–O(2) was –9.18(13)°), which led to
steric repulsion between the ortho substituents of the
aromatic ring. This was evidenced by the shortened
intramolecular contact N(4)···O(1) 2.60 Å (sum of van der
Waals radii 2.79 Å)11 and the increase of valence angles
N(4)–C(15)–C(16) 121.98(16)°, C(15)–C(16)–N(5) 120.19(6)°,
and N(5)–C(16)–C(17) 118.23(16)°.
The elimination of amide group with the formation of
aryl hydrazones 7а,b occurred in the presence of a
significant amount of concentrated sulfuric acid (Scheme 4).
1
According to Н data acquired in DMSO-d6, compounds
7a,b existed as single isomers assumed to be the Е-isomer,
indirectly indicated by the chemical shifts of NH protons at
10.77 and 10.18 ppm, respectively.10
The structures of azo compounds 4a–d were proposed
based on the analysis of IR and 1Н NMR spectra, as well as
mass spectra. X-ray structural analysis was performed for
compound 4с, confirming the proposed structure (Fig. 1).
Two cyclohexene rings in the structure 4с formed a distorted-
chair conformation with C(3), C(4), C(10), and C(11) atoms
deviating from the median plane of other ring atoms by
An additional structural proof for the synthesized azo
compounds can be obtained from the mass spectral
fragmentation patterns, presented for the example of
compound 4с (FAB ionization) (Scheme 5).
Scheme 4
NaNO2, AcOH
N
N
HCl (for 6a,b)
or H2SO4 (for 7a,b)
H2N
N N
O
H2N
O
Ar
5
6 a (60%)
b (60%)
ArN2+ X–
ArNH2
0°C, 10 min
AcOH, 0°C – rt
15 min
N
N
NH
Ar
6 a Ar = 4-MeC6H4, b Ar = Ph; 7 a Ar = 2-O2NC6H4, b Ar = 4-O2NC6H4;
X– = Cl– (for 6a,b), X = HSO4– (for 7a,b)
7 a (55%)
b (58%)
328

Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
Scheme 5
data for the reaction mixture showed not only signals of
compounds 2 (tR 1.02 min) and 8 (tR 1.27 min), but also a
signal with m/z 423.1 [M+Н]+ (tR 1.65 min), corresponding
to a compound generated by recombination of two
cyanoacridine radicals. We were able to isolate this product
as individual compound. Based on the analysis of 1Н NMR
and mass spectra, we identified its structure as compound
11 (Scheme 6).
H+
N
Path II
Path I
NC N N
NO2
.
NO2
4c
–
–N2
m/z 362
(18%)
Scheme 6
–N2
AcNMe2
~150°C
H+
H+
10–15 min
.
2
2
N
NO2
N
N
N
.
–2N2
N
NC
NC N N
CN
–2Ar·
CN
Ar
m/z 212
(100%)
m/z 334
(16%)
4a–h
The major fragmentation route for these compounds is
CN
N
NC
the elimination of nitrogen molecule and aryl radical,
forming radical ions with m/z 212 (100%) (Route I). The
elimination of nitrogen molecule with further
recombination of the radical intermediates (leading to
nonradical ions with m/z 334 (16%) for compound 4c
(Route II)) was found to be a minor mode of
fragmentation. We should note that fragmentation
according to Route II was not observed for compound 4а.
The obtained azo compounds 4a–h decomposed with
elimination of nitrogen molecule also when heated to 140–
155°C. We studied the thermal decomposition of these
compounds by heating in various solvents. Thus,
thermolysis of compound 4а in refluxing p-xylene gave the
following products according to GC-MS: octahydro-
acridine-4-carbonitrile 2 (retention time tR 3.97 min,
m/z 212 [M]+), dehydrogenated analog 8 (tR 4.61 min,
m/z 210 [M]+), and products from aryl radical reactions,
compounds 9 and 10 (tR 3.10 and 3.35 min, m/z 227 [M]+).
The obtained compounds could not be isolated in
analytically pure form.
30%
11
As shown above, the mutual influence of pyridine ring
and nitrile group in compound 2 sufficiently increased the
reactivity of its С-4 atom, enabling reactions with such
electrophilic reagents as diazonium salts. For this reason,
we were interested in studying the behavior of nitrile 2 also
in reactions with other electrophiles. Thus, N,N-dichloro-
amide of p-chlorobenzenesulfonic acid and N-phenyl-
maleimide were used in reactions with nitrile 2. As
expected, the reaction products were compounds 12 and 13,
respectively. Previously we described an analogous
reaction of nitrile 2 with acrylonitrile (Scheme 7).13
Scheme 7
Ph
SO2NCl2
N
O
O
Cl
CH2Cl2
2
NO2
Me
, 4 h
40°C – rt
30 min
DMSO
65%
N
78%
CN
8
Me
10
N
N
NC
O
Cl
NC
NO2
Me
O
12
9
N
13
Ph
Radicals are well known for their high reactivity and
typically do not leave their solvent cage. This results in
reactions with p-xylene, which is capable of forming a
stabilized "benzyl" radical, thus producing compound 9. The
isomeric compound 10 was formed during arylation of
p-xylene according to a Gomberg–Bachmann type reaction.12
In order to avoid solvent participation in the reaction, the
process was performed in N,N-dimethylacetamide. After
thermolysis of compounds 4а–h in this solvent, HPLC-MS
An interesting and unexpected result was obtained from
nitrosation of nitrile 2 with sodium nitrite in acetic acid.
Instead of the expected nitroso compound, a mixture was
obtained that consisted of mostly the nitro derivative 14
and a small amount of dimer 11 (~3%) (Scheme 8). The
structure of reaction products was established based on the
analysis of IR and 1Н NMR spectra, as well as mass spectra
of the isolated mixture.
329

Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
performed on a LECO CHNS-900 instrument. Melting
We conclude that the nitro compound 14 was formed by
oxidation of intermediate nitroso compound, because the
initial reaction mixture immediately after addition of
sodium nitrite to substrate 2 was bright-green, but turned
yellow towards the end of reaction. We were not able to
isolate the nitroso compound. The dimer 11 was clearly
formed by a radical mechanism. The cyanoacridine radical,
which underwent further dimerization, was likely formed
by elimination of hydrogen atom from the nitrile 2 through
reaction with nitrogen dioxide.
points were determined with a Thiele apparatus. The
reaction progress and purity of the obtained compounds were
controlled by TLC on Merck Silicagel 60 F254 plates with 10:1
CHCl3–2-PrOH mobile phase. The HPLC-MS analysis was
performed on an Agilent 1200 instrument, with Rapid
Resolution HT Cartrige 4.6 × 30 mm column, 1.8 µm, Zorbax
SB-C18, DAD and MS detectors, electrospray ionization at
atmospheric pressure. The GC-MS analysis was performed
on a Varian 1200L gas chromato-mass spectrometer (EI
ionization, 70 eV), Optima-5 capillary column (Macherey-
Nagel), stationary phase – 5% phenylpolysiloxane and 95%
dimethylpolysiloxane.
The amide 5 was nitrated analogously, but due to its
lower stability under the reaction conditions, the yield of
nitro derivative 15 did not exceed 10% (Scheme 8).
4-[(E)-(4-Nitrophenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4а). Concentrated (96%)
sulfuric acid (2.77 ml, 0.05 mol) was stirred with overhead
stirrer and cooled with ice bath. Dry sodium nitrite (1.38 g,
0.02 mol) and p-nitroaniline (1.38 g, 0.01 mol) in AcOH
(30 ml) were added, the mixture was stirred for 10 min. A
solution of nitrile 2 (2.12 g, 0.01 mol) in AcOH (15 ml)
was added dropwise to the obtained diazonium salt with
cooling in ice bath. The mixture was stirred for 15 min,
diluted with Н2О (50 ml), and neutralized with 1 N K2CO3
solution to рН 8–9. The yellow precipitate was filtered off
and recrystallized from 2-PrOH. Yield 2.00 g (55%). Yellow
powder. Mp 135–136°C (decomp.). IR spectrum, ν, cm–1:
2929–2857 (–(CH2)n–), 2241 (CN), 1525, 1349 (NO2),
Scheme 8
NaNO2
[O]
AcOH
2
N
N
0°C – rt
30 min
NO
NC NO2
NC
14
(56%)
+ 11 (3%)
NaNO2
AcOH
[O]
5
N
H2N
N
H2N
0°C – rt
30 min
10%
NO
NO2
1
O
O
15
1449 (–N=N–). H NMR spectrum, δ, ppm (J, Hz): 1.65–
2.27 (6Н, m, 2,6,7-СН2); 2.53–2.75 (6Н, m, 1,3,8-СН2);
2.93–2.97 (2Н, m, 5-СН2); 7.45 (1Н, s, H-9); 7.91 (2Н,
Thus, we have shown in this work that the mutual
3
3
d, J = 9.0, H-2,6 Ar); 8.38 (2Н, d, J = 9.0, H-3,5 Ar).
Mass spectrum, m/z (Irel, %): 362 [М+H]+ (26), 212
[М+H–N2C6H4NO2]+ (56). Found, %: С 66.56; Н 5.34;
N 19.42. C20H19N5O2. Calculated, %: С 66.47; Н 5.30;
N 19.38.
influence of pyridine ring and nitrile (amide) group
increased the reactivity of nitrile and amide derived from
1,2,3,4,5,6,7,8-octahydroacridine-4-carboxylic acid at position
4, allowing to perform reactions with various electrophilic
reagents in acidic and neutral media. We also established
that nitrosation of these compounds with nitrous acid gave
nitrile and amide of 4-nitro-1,2,3,4,5,6,7,8-octahydro-
acridine-4-carboxylic acid.
Compounds 4b–f, 7а,b were obtained analogously;
H2SO4 was substituted with an equivalent excess of conc.
HCl for the preparation of compounds 4g,h, 6а,b.
4-[(E)-(3-Nitrophenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4b). Yield 65%. Yellow
powder. Mp 140–141°C (decomp.). IR spectrum, ν, cm–1:
2935 (–(CH2)n–), 2231 (CN), 1535, 1351 (NO2), 1453
Experimental
IR spectra were recorded on a Perkin Elmer Spectrum
1
One spectrophotometer in KBr pellets. Н NMR spectra
1
(–N=N–). H NMR spectrum, δ, ppm: 1.65–2.27 (6Н, m,
were acquired on Bruker Avance II 400 (400 MHz)
(compounds 4c,d,g,h, 6a,b, 7a, 11, 13, 14) or Varian VXR-
200 (200 MHz) instruments (the rest of the compounds).
Solvents: 10:1 DMSO-d6–CCl4, (compound 13) or DMSO-d6
(the rest of the compounds), internal standard TMS. One-
dimensional 13C, as well as 13С DEPT-135 NMR spectra
were acquired on a Bruker Avance II 400 instrument at
100 MHz (compound 13) in 10:1 DMSO-d6–CCl4 solution,
internal standard TMS. Mass spectra with EI ionization
were recorded on an MX1321 instrument (compounds 11,
12, 15) with direct introduction of sample into the ion
source at ionization chamber temperature 200°С and ionizing
electron energy of 70 eV. The FAB spectra of other
compounds were recorded on a VG7070 spectrometer.
Desorption of ions from sample solution in m-nitrobenzyl
alcohol and thioglycerol (compound 4g) was performed
with a beam of 8 keV argon atoms. Elemental analysis was
2,6,7-СН2); 2.53–2.75 (6Н, m, 1,3,8-СН2); 2.90–2.97 (2Н,
m, 5-СН2); 7.45 (1Н, s, H-9); 7.82–7.91 (1Н, m, H-5 Ar);
8.21–8.25 (1Н, m, H-6 Ar); 8.28–8.34 (1Н, m, H-2 Ar);
8.38–8.46 (1Н, m, H-4 Ar). Mass spectrum, m/z (Irel, %): 362
[М+H]+ (10), 334 [М+H–N2]+ (6), 212 [М+H–N2C6H4NO2]+
(100). Found, %: С 66.58; Н 5.35; N 19.45. C20H19N5O2.
Calculated, %: С 66.47; Н 5.30; N 19.38.
4-[(E)-(2-Nitrophenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4c). Yield 61%. Red
needles. Mp 142–143°C (decomp.). IR spectrum, ν, cm–1:
2957 (–(CH2)n–), 2236 (CN), 1515, 1345 (NO2), 1452
1
(–N=N–). H NMR spectrum, δ, ppm (J, Hz): 1.66–1.82
(4Н, m, 6,7-СН2); 1.91–2.01 (1Н, m, 2-СНax); 2.15–2.24
(1Н, m, 2-CНeq); 2.38–2.48 (2Н, m, 1(8)-СН2); 2.61–2.79
(4Н, m, 3-СН2, 8(1)-СН2); 2.89–2.93 (2Н, m, 5-СН2); 7.35
(1Н, d, 3J = 7.7, H-6 Ar); 7.42 (1Н, s, H-9); 7.71–7.90 (2Н,
330

Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
m, H-4,5 Ar); 8.14 (1Н, d, 3J = 7.8, H-3 Ar). Mass spectrum,
1H NMR spectrum, δ, ppm (J, Hz): 1.66–1.79 (4Н, m,
6,7 СН2); 1.88–2.01 (1Н, m, 2-CНax); 2.13–2.25 (1Н, m,
2-CНeq); 2.37 (3Н, s, CH3); 2.38–2.48 (2Н, m, 1(8)-СН2);
2.55–2.70 (2Н, m, 8(1)-СН2); 2.71–2.76 (2Н, m, 3-СН2);
2.92 (2Н, t, 3J = 6.2, 5-СН2); 7.35 (2Н, d, 3J = 7.6, H-3,5 Ar);
m/z (Irel, %): 362 [М+H]+ (18), 334 [М+H–N2]+ (16), 212
[М+H–N2C6H4NO2]+ (100). Found, %: С 66.55; Н 5.34;
N 19.43. C20H19N5O2. Calculated, %: С 66.47; Н 5.30; N 19.38.
4-[(E)-(2-Methyl-4-nitrophenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4d). Yield 70%. Yellow
powder. Mp 145–146°C (decomp.). IR spectrum, ν, cm–1:
2934 (–(CH2)n–, CH3), 2234 (CN), 1526, 1344 (NO2), 1452
(–N=N–). 1H NMR spectrum, δ, ppm (J, Hz): 1.66–1.82 (4Н,
m, 6,7-СН2); 1.91–2.01 (1Н, m, 2-CНax); 2.15–2.24 (1Н, m,
2-CНeq); 2.38–2.48 (2Н, m, 1(8)-СН2); 2.56–2.65 (2Н, m,
8(1)-СН2); 2.68–2.77 (5Н, m, 3-СН2, CH3); 2.89–2.95 (2Н,
m, 5-СН2); 7.44 (1Н, s, H-9); 7.73 (1Н, d, 3J = 8.5, H-6 Ar);
7.91 (1Н, d, 4J = 2.4, H-3 Ar); 8.29 (1Н, dd, 3J = 8.5, 4J = 2.4,
H-5 Ar). Mass spectrum, m/z (Irel, %): 376 [М+H]+ (13), 348
[М+H–N2]+ (15), 212 [М+H–N2C6H3(СН3)NO2]+ (100).
Found, %: С 67.27; Н 5.69; N 18.72. C21H21N5O2.
Calculated, %: С 67.18; Н 5.64; N 18.65.
3
7.41 (1Н, s, H-9); 7.61 (2Н, d, J = 7.6, H-2,6 Ar). Mass
spectrum, m/z (Irel, %): 331 [М+H]+ (12), 303 [М+H–N2]+
(9), 212 [М+H–N2С6Н4Ме]+ (67). Found, %: С 76.43;
Н 6.80; N 17.05. C21H22N4. Calculated, %: С 76.33;
Н 6.71; N 16.96.
4-[(E)-(4-Methylphenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carboxamide (6а). Yield 60%. Yellow
powder. Mp 145–146°C (decomp.). IR spectrum, ν, cm–1:
3433 (NH21), 2930–2852 (–(CH2)n–, CH3), 1678 (СО), 1436
(–N=N–). H NMR spectrum, δ, ppm (J, Hz): 1.52–1.78
(6Н, m); 2.05–2.12 (1Н, m); 2.34 (3H, s, CH3); 2.51–2.73
(7Н, m); 7.19 (1H, s, H-9); 7.28 (2Н, d, 3J = 8.4, H-3,5 Ar);
7.54 (1Н, br. s) and 7.58 (1Н, br. s, NH2); 7.56 (2Н, d,
3J = 8.4, H-2,6 Ar). Mass spectrum, m/z (Irel, %): 349
[М+H]+ (21), 230 [М+H–N2C6H4Me]+ (100). Found, %:
С 72.28; Н 6.88; N 16.02. C21H24N4О. Calculated, %:
С 72.39; Н 6.94; N 16.08.
4-[(E)-Phenyldiazenyl]-1,2,3,4,5,6,7,8-octahydro-
acridine-4-carboxamide (6b). Yield 60%. Yellow
powder. Mp 140–141°C (decomp.). IR spectrum, ν, cm–1:
3451 (NH2), 2919–2828 (–(CH2)n–), 1685 (СО), 1452 (–N=N–).
1H NMR spectrum, δ, ppm: 1.52–1.78 (6Н, m); 2.05–2.15
(1Н, m); 2.33–2.43 (1Н, m); 2.56–2.72 (6Н, m); 7.20 (1Н,
s, H-9); 7.45–7.51 (3Н, m, Н Ph); 7.56 (1Н, s) and 7.58
(1H, s, NH2); 7.62–7.68 (2Н, m, Н Ph). Mass spectrum, m/z
(Irel, %): 335 [М+H]+ (24), 230 [М+H–N2Ph]+ (100).
Found, %: С 71.95; Н 6.70; N 16.81. C20H22N4О.
Calculated, %: С 71.83; Н 6.63; N 16.75.
4-[(E)-(4-Methyl-2-nitrophenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4e). Yield 70%. Yellow
powder. Mp 145–146°C (decomp.). IR spectrum, ν, cm–1:
2944 (–(CH2)n–, CH3), 2235 (CN), 1520, 1348 (NO2), 1454
1
(–N=N–). H NMR spectrum, δ, ppm (J, Hz): 1.65–2.27
(6Н, m, 2,6,7-СН2); 2.44 (3Н, s, CH3); 2.53–2.78 (6Н, m,
1,3,8-СН2); 2.87–2.93 (2Н, m, 5-СН2); 7.31 (1Н, d, 3J = 8.2,
H-5 Ar); 7.42 (1Н, s, H-9); 7.62 (1Н, d, 3J = 8.2, H-6 Ar); 7.96
(1Н, s, H-3 Ar). Mass spectrum, m/z (Irel, %): 376 [М+H]+
(26), 348 [М+H–N2]+ (37), 212 [М+H–N2C6H3(СН3)NO2]+
(100). Found, %: С 67.11; Н 5.58; N 18.60. C21H21N5O2.
Calculated, %: С 67.18; Н 5.64; N 18.65.
4-[(E)-(4-Cyano-1,2,3,4,5,6,7,8-octahydroacridin-4-yl)-
diazenyl]benzenesulfonamide (4f). Yield 65%. Pale-
yellow powder. Mp 180–181°C (decomp.). IR spectrum, ν,
cm–1: 3390 (NH2), 2923 (–(CH2)n–), 2230 (CN), 1454 (–N=N–),
(2-Nitrophenyl)hydrazone of (4Е)-2,3,5,6,7,8-hexa-
hydroacridin-4(1H)-one (7а). Yield 55%. Red powder.
Mp 236–238°C. IR spectrum, ν, cm–1: 3310 (NH), 2932–
2858 (–(CH2)n–), 1614 (C=N), 1578, 1328 (NO2). 1H NMR
spectrum, δ, ppm (J, Hz): 1.65–1.95 (6Н, m, 2,6,7-СН2);
1
1350, 1165–1152 (SO2). H NMR spectrum, δ, ppm (J, Hz):
1.65–2.26 (6Н, m, 2,6,7-СН2); 2.53–2.75 (6Н, m, 1,3,8-СН2);
2.92–2.97 (2Н, m, 5-СН2); 7.45 (1Н, s, H-9); 7.55 (2Н, s,
3
NH2); 7.86 (2Н, d, J = 7.9, H-3,5 Ar); 7.98 (2Н, d, 3J = 7.9,
H-2,6 Ar). Mass spectrum, m/z (Irel, %): 396 [М+H]+ (7), 368
[М+H–N2]+ (15), 212 [М+H–N2C6H4SO2NH2]+ (96). Found,
%: С 60.89; Н 5.41; N 17.75. C20H21N5O2S. Calculated, %:
С 60.74; Н 5.35; N 17.71.
3
2.62–2.88 (8Н, m, 1,3,5,8-СН2); 6.94 (1H, t, J = 7.7, H-4
3
Ar); 7.25 (1Н, s, H-9); 7.71 (1H, t, J = 8.0, H-5 Ar); 8.02
3
3
(1H, d, J = 8.3, H-6 Ar); 8.13 (1H, d, J = 8.7, H-3 Ar);
10.77 (1H, s, NH). Mass spectrum, m/z (Irel, %): 337
[М+Н]+ (100). Found, %: С 67.96; Н 6.07; N 16.73.
C19H20N4О2. Calculated, %: С 67.84; Н 5.99; N 16.65.
(4-Nitrophenyl)hydrazone of (4Е)-2,3,5,6,7,8-hexahydro-
acridin-4(1H)-one (7b). Yield 58%. Yellow powder. Mp
250–253°C. IR spectrum, ν, cm–1: 3436 (NH), 2937–2856
4-[(E)-Phenyldiazenyl]-1,2,3,4,5,6,7,8-octahydro-
acridine-4-carbonitrile (4g). Yield 40%. Yellow powder.
Mp 125–126°C (decomp.). IR spectrum, ν, cm–1: 2931–
1
2861 (–(CH2)n–), 2242 (CN), 1450 (–N=N–). H NMR
spectrum, δ, ppm (J, Hz): 1.66–1.82 (4Н, m, 6,7-СН2); 1.91–
2.01 (1Н, m, 2-CНax); 2.15–2.25 (1Н, m, 2-CНeq); 2.36–
2.48 (2Н, m, 1(8)-СН2); 2.58–2.70 (2Н, m, 8(1)-СН2); 2.71–
1
(–(CH2)n–), 1597 (C=N), 1567, 1319 (NO2). H NMR
spectrum, δ, ppm (J, Hz): 1.64–1.92 (6Н, m, 2,6,7-СН2);
2.62–2.88 (8Н, m, 1,3,5,8-СН2); 7.23 (1H, s, H-9); 7.36
3
2.77 (2Н, m, 3-СН2); 2.93 (2Н, t, J = 6.2, 5-СН2); 7.42
3
3
(1Н, s, H-9); 7.52–7.57 (3Н, m, Н Ph); 7.66–7.72 (2Н, m,
Н Ph). Mass spectrum, m/z (Irel, %): 317 [М+H]+ (12), 289
[М+H–N2]+ (5), 212 [М+H–N2Ph]+ (100). Found, %:
С 75.81; Н 6.30; N 17.66. C20H20N4. Calculated, %:
С 75.92; Н 6.37; N 17.71.
4-[(E)-(4-Methylphenyl)diazenyl]-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (4h). Yield 42%. Yellow
powder. Mp 133–134°C (decomp.). IR spectrum, ν, cm–1:
2937–2835 (–(CH2)n–, CH3), 2232 (CN), 1454 (–N=N–).
(2Н, d, J = 9.1, H-2,6 Ar); 8.13 (2Н, d, J = 9.1, H-3,5
Ar); 10.18 (1H, s, NH). Mass spectrum, m/z (Irel, %): 337
[М+Н]+ (100). Found, %: С 67.98; Н 6.05; N 16.72.
C19H20N4О2. Calculated, %: С 67.84; Н 5.99; N 16.65.
Thermolysis of compound 4а. Method I. A solution of
compound 4а (1 g, 3 mmol) in p-xylene (7 ml) was
refluxed for 10–15 min, then the mixture was cooled to
room temperature, diluted with n-hexane (5 ml), and
analyzed by GC-MS.
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Chemistry of Heterocyclic Compounds 2015, 51(4), 327–333
Thermolysis of compounds 4а–h. Method II.
386 [М+Н]+ (100), 359 [М+Н–HCN]+ (6). Found, %:
С 74.90; Н 6.09; N 10.97. C24H23N3О2. Calculated, %:
С 74.78; Н 6.01; N 10.90.
Thermolysis was performed analogously to method I, using
N,N-dimethylacetamide as solvent and maintaining the
reaction temperature at approximately 150°C. After cooling
to room temperature, water was added to the reaction
mixture, and the precipitate that formed was filtered off.
The obtained product was analyzed without purification by
HPLC-MS or recrystallized from n-hexane, giving
2,2',3,3',5,5',6,6',7,7',8,8-dodecahydro-4,4'-diacridine-
4,4'(1H,1'H)-dicarbonitrile (11). Yield 30%. Orange
powder. Mp 130–133°C. 1H NMR spectrum, δ, ppm: 1.52–
1.93 (12Н, m, 6СН2); 2.52–2.87 (16Н, m, 8СН2); 7.23 (2Н,
s, H-9,9'). Mass spectrum, m/z (Irel, %): 422 [М]+ (11).
Found, %: С 79.79; Н 7.25; N 13.35. C28H30N4. Calculated,
%: С 79.59; Н 7.16; N 13.26.
4-Chloro-1,2,3,4,5,6,7,8-octahydroacridine-4-carbo-
nitrile (12). N,N-Dichloroamide of p-chlorobenzenesulfonic
acid (2.60 g, 0.01 mol) was dissolved in CH2Cl2 (5 ml) and
gradually added to a solution of compound 2 (2.12 g,
0.01 mol) in CH2Cl2 (5 ml), resulting in exothermic effect
that brought the reaction mixture to boiling. The mixture
was vigorously stirred for 30 min, then treated with 20%
Na2SO3 solution (5 ml). The organic layer was separated,
dried over Na2SO4, and evaporated to dryness under
vacuum. The residue was recrystallized from n-hexane.
Yield 1.92 g (78%). Colorless powder. Mp 80–83°C. IR
spectrum, ν, cm–1: 2983–2831 (–(CH2)n–), 2245 (CN).
1H NMR spectrum, δ, ppm: 1.53–2.03 (6Н, m, 2,6,7-СН2);
2.55–2.93 (8Н, m, 1,3,5,8-СН2); 7.35 (1Н, s, H-9). Mass
spectrum, m/z (Irel, %): 248 [М(37Cl)]+ (4), 246 [М(35Cl)]+
(12), 211 [М–Cl]+ (100), 184 [М–Cl–HCN]+ (37). Found,
%: С 68.05; Н 6.08; N 11.08. C14H15ClN2. Calculated, %:
С 68.15; Н 6.13; N 11.35.
4-Nitro-1,2,3,4,5,6,7,8-octahydroacridine-4-carbo-
nitrile (14). A solution of compound 2 (2.12 g, 10 mmol) in
AcOH (20 ml) was stirred and cooled in ice bath, while dry
NaNO2 (3.00 g, 43 mmol) was gradually added. The mixture
was maintained at room temperature for 30 min, then
poured onto crushed ice and neutralized with 15%
ammonia solution to рН 8–9. The precipitate that formed
was filtered off and recrystallized from МеОН. The
product was colorless powder (1.5 g), containing
compound 14 (56% yield) with impurity of dimer 11 (~3%
1
yield), according to Н NMR data. Mp 125–128°C. IR
spectrum, ν, cm–1: 2934–2865 (–(CH2)n–), 2234 (CN),
1
1560, 1363 (NO2). H NMR spectrum, δ, ppm: 1.68–2.01
(7Н, m); 2.68–2.97 (9Н, m); 7.23 (0.05Н, s, H-9,9' (11));
7.47 (0.97Н, s, H-9 (14)). Mass spectrum, m/z (Irel, %):
compound 14 – 258 [М+H]+ (4), 212 [М+H–NO2]+ (100);
compound 11 – 423 [М+H]+ (6).
4-Nitro-1,2,3,4,5,6,7,8-octahydroacridine-4-carbox-
amide (15) was obtained analogously to compound 14.
Yield 10%. Colorless powder. Mp 185–188°C (МеОН).
IR spectrum, ν, cm–1: 3295, 3158 (NH2), 2958–2834
(–(CH2)n–), 1707 (СО), 1541, 1370 (NO2). 1H NMR
spectrum, δ, ppm: 1.49–1.82 (6Н, m, 2,6,7-СН2); 2.62–2.83
(8Н, m, 1,3,5,8-СН2); 7.32 (1Н, s, H-9); 7.38 (1Н, s) and
7.62 (1Н, s, NH2). Mass spectrum (EI), m/z (Irel, %): 229
[М–NO2]+ (94). Mass spectrum (FAB), m/z (Irel, %): 276
[М+H]+ (24), 230 [М+H–NO2]+ (100). Found, %: С 60.93;
Н 6.14; N 15.17. C14H17N3О3. Calculated, %: С 61.08;
Н 6.22; N 15.26.
X-ray structural study of compound 4с (C20H19N5O2,
M 361.40) was performed at 298 K on an Xcalibur 3
diffractometer. Crystals of compound 4с were monoclinic,
a 15.8978(6), b 12.2313(5), c 9.7569(5) Å; β 105.519(5)°;
V 1828.07(15)Å3, space group P21/c; Z 4; dcalc 1.313 g/cm3.
A total of 18841 reflections were collected (2θmax 58°),
including 4357 independent, Rint 0.036. The structure was
solved directly and refined with full matrix method of least
squares by F2 using the SHELX 2013 software suite.14 The
hydrogen atom positions were determined by differential
map of electron density and refined by the "rider" model
with Uiso = 1.2Ueq of the carrier atom. The final probability
factors: wR2 0.133 (by all independent reflections),
R1 0.060 (by 2966 reflections with I > 2σ(I)), S 1.07.
Crystallographic data were deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1045557).
4-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-1,2,3,4,5,6,7,8-octa-
hydroacridine-4-carbonitrile (13). N-Phenylmaleimide
(1.73 g, 0.01 mol) was added to a solution of compound 2
(2.12 g, 0.01 mol) in DMSO (5 ml). The reaction mixture
was refluxed for 4 h, cooled to room temperature, diluted
with a small amount of water and allowed to crystallize for
1 day. The precipitate that formed was filtered off. Yield
2.5 g (65%). Beige needles. Mp 154–156°C (DMF–Н2О). IR
spectrum, ν, cm–1: 2938–2854 (–(CH2)n–), 2234 (CN), 1711
1
(CO). H NMR spectrum, δ, ppm (J, Hz): 1.59–2.09 (6Н,
m, 3СН2); 2.35–2.40 (1Н, m); 2.51–2.85 (7Н, m); 3.02–
3.16 (1Н, m); 3.33–3.43 (1Н, m); 3.70–3.75 (1Н, m); 6.91
3
(2Н, d, J = 7.5, H-2,6 Ph); 7.23 (1Н, s, H-9); 7.31–7.42
(3Н, m, H-3,4,5 Ph). 13C NMR spectrum, δ, ppm: 19.7
(СН2); 22.1 (СН2); 22.3 (СН2); 26.9 (СН2); 27.6 (СН2);
31.4 (СН2); 32.3 (СН2); 34.9 (СН2 pyrrolidine); 43.2 (C-4);
45.7 (CH pyrrolidine); 120.8 (CN); 126.1 (CH Ph); 127.6
(CH Ph); 128.1 (CH Ph); 129.4 (C Ph); 131.8 (C Py); 131.9
(C Py); 138.1 (C-9); 148.1 (C Py); 154.6 (C Py); 174.2
(CO); 174.7 (CO). DEPT-135 13C NMR spectrum, δ, ppm:
19.7* (СН2); 22.1* (СН2); 22.3* (СН2); 26.9* (СН2); 27.6*
(СН2); 31.4* (СН2); 32.3* (СН2); 34.9* (СН2 pyrrolidine);
45.7 (CH pyrrolidine); 126.1 (CH Ph); 127.6 (CH Ph);
128.1 (CH Ph); 138.1 (C-9). Mass spectrum, m/z (Irel, %):
The Supplementary material is available for authorized
users.
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