Spiro heterocyclization of 4-aryl-4-oxobutane-1,1,2,2-tetracarbonitriles to 3H-pyrrole derivatives, 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes

Article abstract of DOI:10.1134/S1070428013060110

4-Aryl-3-methyl-4-oxobutane-1,1,2,2-tetracarbonitriles reacted with morpholine to give 8-amino-3-aryl-1-imino-4-methyl-6-(morpholin-4-yl)-2-oxa-7- azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles.

Full text of DOI:10.1134/S1070428013060110

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 6, pp. 864–866. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © M.Yu. Belikov, O.V. Ershov, I.V. Lipovskaya, S.V. Fedoseev, O.E. Nasakin, 2013, published in Zhurnal Organicheskoi Khimii,
2013, Vol. 49, No. 6, pp. 880–882.
Spiro Heterocyclization of 4-Aryl-4-oxobutane-
1,1,2,2-tetracarbonitriles to 3H-Pyrrole Derivatives,
2-Oxa-7-azaspiro[4.4]nona-3,6,8-trienes
M. Yu. Belikov, O. V. Ershov, I. V. Lipovskaya, S. V. Fedoseev, and O. E. Nasakin
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
e-mail: belikovmil@mail.ru
Received October 4, 2012
Abstract—4-Aryl-3-methyl-4-oxobutane-1,1,2,2-tetracarbonitriles reacted with morpholine to give 8-amino-3-
aryl-1-imino-4-methyl-6-(morpholin-4-yl)-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles.
DOI: 10.1134/S1070428013060110
4-Oxoalkane-1,1,2,2-tetracarbonitriles are exten-
sively studied representatives of the series of poly-
nitrile compounds. Derivatives of 4-oxoalkane-1,1,2,2-
tetracarbonitriles are known as potential antitumor
agents [1] and coordination polymers with interesting
topology [2].
showed that the reaction of 4-oxoalkane-1,1,2,2-tetra-
carbonitriles with morpholine leads to 5-amino-2-
(morpholin-4-yl)-3H-pyrrole-3,4-dicarbonitriles [8, 9]
and found that nitrogen-centered nucleophiles prefer-
ably add to the β-cyano groups of polyelectrophilic
tetranitriles. The resulting compounds are represen-
tatives of a poorly explored class of aza heterocycles,
3H-pyrroles, which may be regarded as nitrogen-con-
taining cyclopentadiene analogs. Despite limited pub-
lished data, some 3H-pyrroles were found to exhibit
antimicrobial and antitumor activity [10–12].
We now perform extensive studies on the trans-
formations of 4-oxoalkane-1,1,2,2-tetracarbonitriles
by the action of nitrogen-centered nucleophiles [3].
4-Oxoalkane-1,1,2,2-tetracarbonitriles were reported to
react with ammonia and amines to form 3-amino-7-
oxo-4,6-diazabicyclo[3.2.1]oct-2-ene-1,2-dicarbo-
nitriles [4], 3-amidinio-2-aminopyridine-4-carbox-
ylates [5], diethylammonium 3,4-dicyano-5,6,7,8-tetra-
hydroquinolin-2-olates [6], and ammonium 4-aryl-4-
oxo-1,1,2-tricyanobut-2-en-1-ides [7]. We recently
With a view to synthesize new functionally substi-
tuted 3H-pyrrole derivatives, we extended the series of
4-oxoalkane-1,1,2,2-tetracarbonitrile substrates and ex-
amined their reaction with morpholine in more detail.
The reactions of 4-aryl-3-methyl-4-oxobutane-1,1,2,2-
Scheme 1.
O
O
NC
Me
CN
CN
NC
Me
CN
NH
NH2
CN
CN
+
Ar
Ar
O
O
O
CN
Ia–Ic
A
NH
Ar
NH
CN
O
Ar
NH
CN
O
NH2
Me
NH2
NH
O
Me
N
N
CN
–
CN
O
O
B
IIa–IIc
Ar = Ph (a), 4-ClC6H4 (b), 4-MeC6H4 (c).
864

SPIRO HETEROCYCLIZATION OF 4-ARYL-4-OXOBUTANE-1,1,2,2-TETRACARBONITRILES
865
tetracarbonitriles Ia–Ic with morpholine gave no
analogs of 5-amino-2-(morpholin-4-yl)-3H-pyrrole-
3,4-dicarbonitriles described in [8, 9]. In this case, the
process involved more profound transformation with
participation of the carbonyl and β-cyano group, and
the products were previously unknown 8-amino-3-
aryl-1-imino-4-methyl-6-(morpholin-4-yl)-2-oxa-7-
azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles IIa–IIc
(yield 65–71%, Scheme 1) as representatives of rare
spiro fused 3H-pyrroles.
Presumably, CH acids Ia–Ic initially react with
morpholine to give salts A. Structural analogs of salts
A containing metal or ammonium cations were report-
ed previously [2, 7, 13]. In the next step, intramolec-
ular cyclization of A yields iminofurans B which
undergo further transformations in the presence of
excess morpholine, eventually leading to formation of
spiro heterocyclic compounds IIa–IIc. The possibility
for formation of iminofurans from 4-oxoalkane-
1,1,2,2-tetracarbonitriles under basic conditions was
demonstrated in [14, 15]. It is also known that imino-
furans structurally similar to intermediates B are con-
verted into 3H-pyrroles in the presence of morpholine
[8]. As we showed previously [8, 9], 3H-pyrroles IIa–
IIc are formed via transformation of just β- rather than
γ-cyano groups in the initial 4-oxoalkane-1,1,2,2-tetra-
carbonitriles, which is due to reduced electrophilicity
of the γ-cyano groups in reactions with basic reagents.
centered nucleophiles, which leads to the formation of
polyfunctionalized spiro-fused 3H-pyrrole derivatives,
8-amino-3-aryl-1-imino-4-methyl-6-(morpholin-4-yl)-
2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles.
EXPERIMENTAL
The progress of reactions was monitored, and the
purity of products was checked, by TLC on Silufol
UV-254 plates; spots were visualized under UV light,
by treatment with iodine vapor, and by thermal decom-
position. The IR spectra were recorded on an FSM-
1202 spectrometer with Fourier transform from
samples dispersed in mineral oil. The 1H NMR spectra
were measured on a Bruker DRX-500 spectrometer at
500.13 MHz using DMSO-d6 as solvent and tetra-
methylsilane as internal reference. The elemental com-
positions were determined on a Laboratorni Přistroje
analyzer. The mass spectra (electron impact, 70 eV)
were obtained on a Finnigan MAT INCOS-50 mass
spectrometer.
Spiro-fused 3H-pyrroles IIa–IIc (general proce-
dure). A solution of 0.5 mmol of 4-aryl-3-methyl-4-
oxobutane-1,1,2,2-tetracarbonitrile Ia–Ic in 3 ml of
anhydrous ethyl acetate was cooled to –10 to –15°C,
0.087 g (1 mmol) of morpholine was added under
vigorous stirring, and the yellow–orange mixture was
left to stand in a closed vessel at –10 to –15°C. After
3–4 days, the yellowish precipitate was filtered off,
washed on a filter with cold ethyl acetate and diethyl
ether, and dried in a vacuum desiccator.
There are only a few published data on analogs of
IIa–IIc with spiro-fused 3H-pyrrole and furan rings
[16, 17]. The structure of compounds IIa–IIc was
confirmed by their IR, 1H NMR, and mass spectra and
elemental analyses. The mass spectra of IIa–IIc con-
tained the molecular ion peaks with a relative intensity
of 55–93%. According to the IR data, amino and imino
groups (3133–3347 cm–1) and a conjugated cyano
group (strong bands at 2167–2173 cm–1) were present
in the molecules of IIa–IIc. In the 1H NMR spectra we
observed singlets from protons in the methyl group on
the furan ring (δ 1.75–1.80 ppm) and signals from
amino groups (δ 7.13–7.28 ppm), aromatic protons
(δ 7.30–7.65 ppm), and =NH protons (8.91–9.23 ppm).
Protons in the morpholine substituent resonated as
8-Amino-1-imino-4-methyl-6-(morpholin-4-yl)-
3-phenyl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-
carbonitrile (IIa). Yield 0.122 g (71%), mp 158–
159°C (decomp.). IR spectrum, ν, cm–1: 3133–3347
1
(NH, NH2), 2167 (C≡N). H NMR spectrum, δ, ppm:
1.77* s and 1.80 s (3H, CH3); 3.10–3.80 m (8H,
morpholine); 7.15 s and 7.26* s (2H, NH2); 7.44–
7.63 m (5H, Harom); 8.95 s and 9.16* s (1H, NH);
isomer ratio 59:41. Mass spectrum: m/z 349 (Irel 93%)
[M]+. Found, %: C 65.39; H 5.38; N 19.96. C19H19N5O2.
Calculated, %: C 65.32; H 5.48; N 20.04. M 349.39.
8-Amino-3-(4-chlorophenyl)-1-imino-4-methyl-6-
(morpholin-4-yl)-2-oxa-7-azaspiro[4.4]nona-3,6,8-
triene-9-carbonitrile (IIb). Yield 0.132 g (69%),
mp 187–188°C (decomp.). IR spectrum, ν, cm–1:
1
broadened signals at δ 3.10–3.80 ppm. The H NMR
spectra of IIa–IIc in DMSO-d6 at room temperature
displayed double sets of signals, indicating formation
of isomer mixtures. We believe that this pattern is
related to E and Z configuration of the C=NH group
where the proton on the nitrogen atom can occupy
different positions.
1
3143–3331 (NH, NH2), 2169 (C≡N). H NMR spec-
trum, δ, ppm: 1.76* s and 1.79 s (3H, CH3); 3.10–
3.75 m (8H, morpholine); 7.17 s and 7.28* s (2H,
Thus we have discovered a new path of the reaction
of 4-oxoalkane-1,1,2,2-tetracarbonitriles with nitrogen-
* Hereinafter, signals belonging to the minor isomer are marked
with an asterisk.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013

BELIKOV et al.
866
5. Nasakin, O.E., Sheverdov, V.P., Ershov, O.V., Moisee-
va, I.V., Lyshchikov, A.N., Khrustalev, V.N., and Anti-
pin, M.Yu., Mendeleev Commun., 1997, vol. 7, p. 112.
6. Belikov, M.Yu., Ershov, O.V., Eremkin, A.V., Kayu-
kov, Ya.S., and Nasakin, O.E., Russ. J. Org. Chem.,
2010, vol. 46, p. 615.
7. Belikov, M.Yu., Ershov, O.V., Eremkin, A.V., Kayu-
kov, Ya.S., and Nasakin, O.E., Russ. J. Org. Chem.,
2010, vol. 46, p. 597.
8. Belikov, M.Yu., Ershov, O.V., Eremkin, A.V., Nasa-
kin, O.E., Tafeenko, V.A., and Nurieva, E.V., Tetra-
hedron Lett., 2011, vol. 52, p. 6407.
NH2); 7.56–7.65 m (4H, Harom); 9.00 s and 9.23* s (1H,
NH); isomer ratio 56:44. Mass spectrum, m/z (Irel, %):
385 (15) [35Cl-M]+, 383 (46) [37Cl-M]+. Found, %:
C 59.56; H 4.69; N 18.14. C19H18ClN5O2. Calculated,
%: C 59.45; H 4.73; N 18.25. M 383.83.
8-Amino-1-imino-4-methyl-3-(4-methylphenyl)-
6-(morpholin-4-yl)-2-oxa-7-azaspiro[4.4]nona-3,6,8-
triene-9-carbonitrile (IIc). Yield 0.118 g (65%),
mp 170–171°C (decomp.). IR spectrum, ν, cm–1:
1
3156–3324 (NH, NH2), 2173 (C≡N). H NMR spec-
trum, δ, ppm: 1.75* s and 1.77 s (3H, 4-CH3); 2.35 s
(3H, 4′-CH3); 3.10–3.80 m (8H, morpholine); 7.13 s
and 7.24* s (2H, NH2); 7.30–7.52 m (4H, Harom); 8.91 s
and 9.10* s (1H, NH); isomer ratio 57:43. Mass spec-
trum: m/z 363 (Irel 55%) [M]+. Found, %: C 66.21;
H 5.73; N 19.18. C20H21N5O2. Calculated, %: C 66.10;
H 5.82; N 19.27. M 363.41.
9. Belikov, M.Yu., Ershov, O.V., Lipovskaya, I.V., Erem-
kin, A.V., and Nasakin, O.E., Russ. J. Org. Chem., 2011,
vol. 47, p. 1426.
10. Padmavathi, V., Radha, L.T., Mahesh, K., and Pad-
maja, A., Chem. Pharm. Bull., 2009, vol. 57, p. 1200.
11. Cirrincione, G., Almerico, A.M., Grimaudo, S.,
Diana, P., Mingoia, F., Barraja, P., and Misuraca, F.,
Farmaco, 1996, vol. 51, p. 49.
12. Cirrincione, G., Almerico, A.M., Dattolo, G., Aiello, E.,
Grimaudo, S., Diana, P., and Misuraca, F., Farmaco,
1992, vol. 47, p. 1555.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 12-03-31335 mol_a).
REFERENCES
13. Nasakin, O.E., Lukin, P.M., and Nikolaev, E.G.,
Zh. Org. Khim., 1987, vol. 23, p. 659.
1. Nasakin, O.E., Lyshchikov, A.N., Kayukov, Ya.S., and
Sheverdov, V.P., Khim.-Farm. Zh., 2000, vol. 34,
no. 4, p. 11.
14. Nasakin, O.E., Sheverdov, V.P., Moiseeva, I.V., Er-
shov, O.V., Chernushkin, A.N., and Tafeenko, V.A.,
Russ. J. Gen. Chem., 1999, vol. 69, p. 291.
2. Carlucci, L., Ciani, G., Proserpio, D.M., and Sironi, A.,
15. Ducker, J.M. and Gunter, M.J., Aust. J. Chem., 1973,
vol. 26, p. 1551.
Angew. Chem., Int. Ed. Engl., 1996, vol. 35, p. 1088.
3. Belikov, M.Yu., Cand. Sci. (Chem.) Dissertation, Kazan.
16. Melsa, P., Cajan, M., Havlas, Z., and Mazal, C., J. Org.
Chem., 2008, vol. 73, p. 3032.
17. Perrin, S., Monnier, K., and Laude, B., Bull. Soc. Chim.
Belg., 1996, vol. 105, p. 777.
2011.
4. Nasakin, O.E., Sheverdov, V.P., Moiseeva, I.V., Lyshchi-
kov, A.N., Ershov, O.V., and Nesterov, V.N., Tetrahedron
Lett., 1997, vol. 38, p. 4455.
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