Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3- ene-4-carbonitriles

Article abstract of DOI:10.1016/j.tetlet.2013.02.043

The domino reactions of 4-oxoalkane-1,1,2,2-tetracarbonitriles with water afford 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-carbonitriles in good yields.

Full text of DOI:10.1016/j.tetlet.2013.02.043

Accepted Manuscript
Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-
ene-4-carbonitriles
Sergey V. Fedoseev, Oleg V. Ershov, Mikhail Yu. Belikov, Konstantin V. Lipin,
Ivan N. Bardasov, Oleg E. Nasakin, Viktor A. Tafeenko
PII:
S0040-4039(13)00278-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.02.043
TETL 42552
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
31 October 2012
30 January 2013
13 February 2013
Please cite this article as: Fedoseev, S.V., Ershov, O.V., Belikov, M.Y., Lipin, K.V., Bardasov, I.N., Nasakin, O.E.,
Tafeenko, V.A., Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-carbonitriles,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.02.043
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Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-
carbonitriles
Sergey V. Fedoseev, Oleg V. Ershov, Mikhail Yu. Belikov, Konstantin V. Lipin, Ivan N.
Bardasov, Oleg E. Nasakin, Viktor A. Tafeenko

Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-
carbonitriles
Sergey V. Fedoseev a, Oleg V. Ershov a, Mikhail Yu. Belikov a, Konstantin V. Lipin a, Ivan N.
Bardasov a*, Oleg E. Nasakin a, Viktor A. Tafeenko b
aUlyanov Chuvash State University, Cheboksary, Moskovsky pr., 15, Russia
bLomonosov Moscow State University, Moscow, Leninskie gory 1, Russia
Abstract — The domino reactions of 4-oxoalkane-1,1,2,2-tetracarbonitriles with water afford 3-
amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-carbonitriles in good yields.
Keywords: Heterocyclic compounds; Cyano compounds; Tetracyanoalkanones; Water; Domino
synthesis; Pyrrolidine; Iminolactone; Spiro compounds.
*
Corresponding
author.
Tel.:
+79083030163;
fax:
+78352450279;
e-mail:
bardasov.chem@mail.ru.
Five-membered azaheterocycles are among natural substances that have important
biological significance. The 5-hydroxypyrrolidine-2-one (5-hydroxylactam) fragment is known
to be a part of many biologically active compounds,1 examples include: integrase inhibitors of
HIV-1,1a-c tyrosine kinase,1d telomerase;1e inhibitors or agonists of the 5-hydroxytryptamine
(serotonin) receptor;1f,g inhibitors of the Mdm2 protein with cellular tumor antigen p53;1h
NMDA-receptor agonists;1i antagonists of CC chemokine receptor type 2,1j endothelin receptor
(oteromycin);1k epolactaene derivatives providing apoptosis-inducing effect on BALL-1 cells;1l
hypnotics from the cyclopyrroline group;1m quinolactacin C;1n as well as agents for the treatment
of disorders of nervous or intellectual activity, memory and mental fatigue.1o They have also
been used as synthetic intermediates in organic synthesis.1p-u
The formation of 5-hydroxylactams is often accomplished by transformation of
polyelectrophilic 4-oxoalkane-1,1,2,2-tetracarbonitriles with nucleophiles.2 Apparently, this is
due to the fact that during "push-pull" tandem nucleophilic addition to the carbonyl group of the
4-oxoalkane-1,1,2,2-tetracarbonitriles, an intermediate A is formed, which can easily undergo
rearrangement into lactam 2,2b containing the 5-hydroxypyrrolidin-2-one fragment (Scheme 1).
Scheme 1. "Push-pull" tandem nucleophilic addition and transformation of
tetracyanoalkanones.
Such processes are favorable as a result of the short distance between the carbonyl oxygen
and the cyanocarbon in the salts of 4-oxoalkane-1,1,2,2-tetracarbonitriles, which is 2.62-2.72 Å
according to the X-ray diffraction analysis,2b,3 being less than the sum of their Van der Waals
radii. Therefore it can be assumed that a n,π *-interaction occurs, which leads to the formation of
a σ-bond.
Using the above approach to obtain new derivatives of 5-hydroxypyrrolidin-2-ones, we
investigated the reaction of 4-oxoalkane-1,1,2,2-tetracarbonitriles 1 with water under base
catalysis. This reaction led to the formation of alkyl or aryl 3-amino-8-hydroxy-1,6-dioxo-2,7-
diazaspiro[4.4]non-3-ene-4-carbonitriles 3a-f in 70-91% yields (Scheme 2 and Table 1).4

Scheme 2. Synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-
carbonitriles 3a-f.
Table 1. Synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-
carbonitriles 3a-f.
Substrate
R1
СН3
СН3
СН3
R2
СН3
С2Н5
СН3
R3
Н
Н
СН3
Н
Product
Yield (%)a
85
91
82
75
78
70
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
СH2СH2CH(t-Bu)СH2
(СH2)4
Ph
СН3
Н
СН3
a Yield of isolated product.
1
13
The structures of compounds 3a-f were confirmed by IR, H and C NMR spectroscopy,
HMBC and by mass spectrometry.5 The infrared spectra exhibited absorption bands due to the
conjugated cyano group at 2185-2188 cm-1, the carbonyl groups at 1611-1723 cm-1 and the
hydroxy and amino groups at 3188-3361 cm-1. The H NMR spectra of products 3a-f exhibited
1
signals at 7.20-7.38 ppm for the amino group, at 10.62-10.89 ppm for the dihydropyrrole NH-
group, at 8.79-9.53 ppm for the tetrahydropyrrole NH-group and other resonances as expected
for the alkyl groups. A feature of the 1H NMR spectra was the wide range in the position of the
13
proton signals due to the OH group (4.79-6.26 ppm). The C NMR spectra of the products
displayed resonances in agreement with the structure. The mass spectra of compounds 3a-f
displayed peaks due to [M - 18]+ fragments, that can be explained by the propensity for easy
elimination of water. The HMBC spectrum of compound 3a contained correlations expected for
the proposed structure, except for a correlation with the proton of the dihydropyrrole NH-group
(Figure 1).
Figure 1. HMBC cross peaks in compound 3a.
An unambiguous determination of the position of the of substituents was achieved by X-
ray diffraction analysis using a single crystal of compound 3е (Figure 2).6 In addition, the X-ray
diffraction data indicated the presence of intramolecular hydrogen bonds between the hydrogen
and oxygen of the 4-OH group, which explains the wide range in the chemical shift of the proton
signals of the OH groups of compounds 3 in the 1H NMR spectra.

Figure 2. ORTEP diagram of (3S*,3aR*,7aS*)-5'-amino-7a-hydroxy-3a-methyl-2,2'-dioxo-
1,1',2,2',3a,4,5,6,7,7a-decahydrospiro[indole-3,3'-pyrrole]-4'-carbonitrile (3e).
Scheme 3. Proposed mechanism for the synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-
diazaspiro[4.4]non-3-ene-4-carbonitriles 3a-f.
Tetracyanoalkanones are known to be moderately strong C-H acids, however we suggest
that the first stage involves nucleophilic addition of the hydroxide to the carbonyl group of 1 to
give B (Scheme 3). Next, a push-pull tandem nucleophilic addition occurs, resulting in
iminofuran anion C. Ring-opening leads to carboxamide D and subsequent cyclization involving
the carboxamide and cyano groups forms the pyrrole E. Similar transformations of
tetracyanoalkanones (C → E) are described in the literature.2 Next addition of the hydroxide
anion forms F, which is followed by intramolecular cyclization to give spirane G. Iminolactone-

lactam rearrangement then leads to diazaspirane H.2a The final product 3 would be formed after
acidification of the reaction mixture.
The structures of spiranes 3a-f contain three asymmetric centers. In our case, according to
1H NMR and 13C NMR spectroscopy of 3a, only one diastereomer was formed. Hence, the
reaction proceeds stereoselectively with 100% diastereomeric purity.
In
conclusion,
3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-
carbonitriles 3a-f have been obtained for the first time as a result of a domino process in one
synthetic operation. The structures of the products contain an important biologically active 5-
hydroxypyrrolidin-2-one fragment.
Acknowledgement
This work was supported by the Russian Foundation for Basic Research as project (№ 12-
03-31335 mol_a).
References and notes
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4. Typical procedure for the preparation of 3-amino-8-hydroxy-1,6-dioxo-2,7-
diazaspiro[4.4]non-3-ene-4-carbonitriles 3а-f. 4-Oxoalkane-1,1,2,2-tetracarbonitrile 1 (10
mmol) was stirred in 20 ml of 5% NaOH aqueous solution of for 1.5-2 h at room
temperature. After completion of the reaction (TLC), the solution was cooled to 0-5 °C and
neutralized with 25% AcOH. The resulting precipitate was filtered and washed with H2O, i-
PrOH and EtOAc.
5. Analytical data for compounds 3a-f. Compound 3a. mp 201-202 °С; 1H NMR (500.13 MHz,
DMSO-d6): δ 0.88 (3Н, d, J = 7.1 Hz, СН3), 1.36 (3Н, s, СН3), 2.26 (1Н, q, J = 7.1 Hz, СН),
4.83 (1Н, s, OН), 7.30 (2Н, s, NH2), 9.12 (1Н, s, NH), 10.75 (1H, s, NH). 13C NMR (125.76
MHz, DMSO-d6): δ 7.57, 24.50, 45.62, 53.00, 64.91, 84.74, 117.33, 157.97, 169.94, 176.48.
IR (mineral oil, cm–1): 3400 (ОН), 3228-3290 (NH), 2186 (CN), 1652-1663 (С=О). MS (EI,
70 eV): m/z (%) 218 [M–18]+ (7). Anal. Calcd for C10H12N4O3: C, 50.84; H, 5.12; N, 23.72.
Found: C, 50.76; H, 5.13; N, 23.76. Compound 3b. mp 205-206 ºС; 1H NMR (500.13 MHz,
DMSO-d6): δ 0.90 (3Н, t, J = 7.5 Hz, СН3), 1.29-1.35 (1Н, m, СН2), 1.40 (3Н, s, СН3),
1.56-1.62 (1Н, m, СН2), 2.12 (1Н, dd, J = 6.4, 8.3 Hz, СН), 4.79 (1Н, s, OН), 7.22 (2Н, s,
NH2), 9.06 (1Н, s, NH), 10.72 (1H, br s, NH). 13C NMR (125.76 MHz, DMSO-d6): δ 12.08,
17.61, 25.40, 51.86, 54.75, 64.31, 84.54, 117.28, 157.33, 169.70, 176.25. IR (mineral oil,
cm–1): 3414 (ОН), 3220-3326 (NH), 2188 (CN), 1665-1696 (С=О). MS (EI, 70 eV): m/z (%)
232 [M–18]+ (44). Anal. Calcd for C11H14N4O3: C, 52.79; H, 5.64; N, 22.39. Found: C,
1
52.81; H, 5.65; N, 22.34. Compound 3c: mp: 283-284 ºС (dec.); H NMR (500.13 MHz,
DMSO-d6): δ 0.90 (3Н, s, СН3), 1.09 (3Н, s, СН3), 1.22 (3Н, s, СН3), 5.66 (1Н, s, OН), 7.26
(2Н, s, NH2), 8.99 (1Н, s, NH), 10.85 (1H, br s, NH). 13C NMR (125.76 MHz, DMSO-d6): δ
16.77, 21.46, 25.19, 48.76, 51.50, 68.69, 87.77, 119.10, 159.07, 169.13, 177.53. IR (mineral
oil, cm–1): 3408 (ОН), 3273-3325 (NH), 2187 (CN), 1711-1690 (С=О). MS (EI, 70 eV): m/z
(%) 232 [M–18]+ (35). Anal. Calcd for C11H14N4O3: C, 52.79; H, 5.64; N, 22.39. Found: C,
1
52.83; H, 5.62; N, 22.41. Compound 3d. mp 231-232 ºС (dec.); H NMR (500.13 MHz,
DMSO-d6): δ 0.83 (9Н, s, 3СН3), 0.84-0.89 (1Н, m, СН), 1.08-1.15 (2Н, m, СН2), 1.56-1.64
(2Н, m, СН2), 1.76-1.80 (1Н, m, СН2), 1.96-2.02 (1Н, m, СН2), 2.33-2-38 (1Н, m, СН),
13
6.26 (1Н, s, OН), 7.20 (2Н, s, NH2), 8.79 (1Н, s, NH), 10.62 (1H, br s, NH). C NMR
(125.76 MHz, DMSO-d6): δ 22.34, 26.97, 27.04, 29.49, 32.16, 32.21, 34.16, 44.15, 50.18,
52.60, 65.34, 84.56, 119.19, 158.89, 170.53, 177.82. IR (mineral oil, cm–1): 3396 (ОН),
3229-3314 (NH), 2187 (CN), 1723-1676 (С=О). MS (EI, 70 eV): m/z (%) 300 [M–18]+ (41).
Anal. Calcd for C16H22N4O3: C, 60.36; H, 6.97; N, 17.60. Found: C, 60.39; H, 6.99; N,
1
17.56. Compound 3e. mp 284-285 ºС (dec.); H NMR (500.13 MHz, DMSO-d6): δ 0.94
(3Н, s, СН3), 1.03-1.16 (1Н, m, СН2), 1.23-1.32 (1Н, m, СН2), 1.41-1.62 (5Н, m, (СН2)3),
1.82-1.88 (1Н, m, СН2), 6.12 (1Н, s, ОН), 7.24 (2Н, s, NН2), 8.84 (1Н, s, NН), 10.87 (1H,
13
br s, NH). C NMR (125.76 MHz, DMSO-d6): δ 14.39, 21.49, 22.55, 32.11, 36.83, 49.34,
51.19, 70.85, 87.12, 119.72, 159.88, 170.73, 177.85. IR (mineral oil, cm–1): 3571 (ОН),
3347-3188 (NH), 2185 (CN), 1679-1611 (С=О). MS (EI, 70 eV): m/z (%) 258 [M–18]+ (20).
Anal. Calcd for C13H16N4O3: C, 56.51; H, 5.84; N, 20.28. Found: C, 56.53; H, 5.85; N,
20.24. Compound 3f. mp 225-226 ºС (dec.); 1H NMR (500.13 MHz, DMSO-d6): δ 0.81 (3Н,
d, J = 7.1 Hz, СН3), 2.32 (1Н, q, J = 7.1 Hz, СН2), 5.51 (1Н, s, OН), 7.34-7.37 (1Н, m,
С6Н5), 7.38 (2Н, s, NH2), 7.40-7.44 (2Н, m, С6Н5), 7.46-7.49 (2Н, m, С6Н5), 9.53 (1Н, s,
NH), 10.89 (1H, br s, NH). 13C NMR (125.76 MHz, DMSO-d6): δ 7.11, 49.06, 53.23, 65.12,
87.62, 117.51, 125.97, 128.39, 128.58, 141.76, 158.27, 170.96, 176.82. IR (mineral oil, cm–
1): 3569 (ОН), 3361-3196 (NH), 2186 (CN), 1689-1622 (С=О). MS (EI, 70 eV): m/z (%)
280 [M–18]+ (26). Anal. Calcd for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78. Found: C,
60.44; H, 4.72 N, 18.76.
6. Crystallographic data (excluding structure factors) for the structure 3e in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supplementary

publication number CCDC 907955. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44 (0) 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk].