Reaction of 2,2,3,3-tetracyanocyclopropyl ketones with sodium and potassium hydroxides

Article abstract of DOI:10.1134/S1070428012110073

Reaction of 2,2,3,3-tetracyanocyclopropyl ketones with water solution of sodium hydroxide after neutralization with sulfuric acid leads to the formation of 4-amino-1-hydroxy-3,6-dioxo-2,3,5,6-tetrahydro-1Hpyrrolo[3,4-c]pyridine-7- carbonitriles. Pivaloylt

Full text of DOI:10.1134/S1070428012110073

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 11, pp. 1447−1455. © Pleiades Publishing, Ltd., 2012.
Original English Text © Ya.S. Kayukov, I.N. Bardasov, S.V. Karpov, O.V. Ershov, O.E. Nasakin, O.V. Kayukova, V.A. Tafeenko, 2012, published in Zhurnal
Organicheskoi Khimii, 2012, Vol. 48, No. 11, pp. 1463−1471.
Reaction of 2,2,3,3-Tetracyanocyclopropyl Ketones
with Sodium and Potassium Hydroxides
Ya. S. Kayukova, I. N. Bardasova, S. V. Karpova, O. V. Ershova, O. E. Nasakina,
O. V. Kayukovab, and V. A. Tafeenkoc
aUl’yanov Chuvash State University, Cheboksary, 428015 Russia
e-mail: kaukovyakov@mail.ru
b Chuvash Agricultural Academy, Cheboksary, Russia
cLomonosov Moscow State University, Moscow, Russia
Received January 23, 2012
Abstract—Reaction of 2,2,3,3-tetracyanocyclopropyl ketones with water solution of sodium hydroxide after
neutralization with sulfuric acid leads to the formation of 4-amino-1-hydroxy-3,6-dioxo-2,3,5,6-tetrahydro-1H-
pyrrolo[3,4-c]pyridine-7-carbonitriles. Pivaloyltetracyanocyclopropane reacts in another way and is converted
into sodium 6a-tert-butyl-3,4-dicyano-5-oxo-1,5,6,6a-tetrahydropyrrolo[2,3-b]pyrrol-2-olate. 1-Benzoyl-1-
methylcyclopropane-2,2,3,3-tetracarbonitrile reacts with the sodium hydroxide with the retention of the three-
membered ring and the formation of 11-methyl-4-phenyl-3,5,9-triazatetracyclo[5.3.1.01,7.04,11]undecane-2,6,8,10-
tetraone.
DOI: 10.1134/S1070428012110073
Pyrrolo[3,4-c]pyridines attract attention as potential
drugs. For instance, substances were found among them
that were ligands of serotonin 5-HT3 receptor [1], caspase
inhibitors 3 [2], and anthelminthics [3]. 1-Hydroxy-3-oxo-
1-pyridylpyrrolo[3,4-c]pyridine fragment is a structural
unit of the adduct INH-NAD that forms in vivo from the
prodrug isoniazid and NAD, and it inhibits the growth
of the infectious agent of tuberculosis [4–8]. Synthetic
analogs of INH-NAD containing the pyrrolo[3,4-c]
pyridine system are tested as potential antitubercular
drugs [4–7]. The known synthetic approaches to the
synthesis of these compounds proceed from pyridine
derivatives and include several stages [4, 6]. We have
developed a preparation method of the pyrrolo[3,4-c]-
pyridine derivatives underlain by a one-step reaction of
available tetracyanocyclopropyl ketones with sodium
hydroxide [9]. In this paper we report on further research
on this reaction.
pyrrolo[3,4-c]pyridine-7-carbonitriles IIa–IIj in 56–77%
yields (Scheme 1). The reaction of the sodium hydroxide
with cyclopropyl ketone Ik proceeds differently. Like
in the case of compounds Ia–Ij the reaction initially
occurred with the ring opening, but the subsequent cy-
clization gave rise to sodium 6a-tert-butyl-3,4-dicyano-
5-oxo-1,5,6,6a-tetrahydropyrrolo[2,3-b]pyrrol-2-olate
(III) that was isolated from the reaction mixture in 92%
yield. We failed to obtain the conjugate acid of salt III
anion since the salt remained practically intact at boiling
in H2SO4 solutions up to 15% concentration, and in more
concentrated solution it suffered slow decomposition
with tarring.
The structure of compounds IIa–IIj was confirmed by
spectral methods. In the 1H NMR spectra the hydroxyl
proton appears as a singlet in the region 6.50–7.48 ppm,
amino group, as a broadened singlet in the range
7.1–7.6 ppm. The proton of NH group of the pyrrole
ring resonates in the region 8.50–9.05 ppm, and NH of
the pyridine (pyridone) ring gives rise to a broadened
singlet at 11.41–11.49 ppm. The signals of the aromatic
substituents appear with their characteristic multiplicity
in the range of common values. The structure of pyrrolo-
The reaction of tetracyanocyclopropyl ketones
Ia–Ik substituted with aromatic, heterocyclic, and
aliphatic moieties with the sodium hydroxide after
neutralization with sulfuric acid results in substituted
4-amino-1-hydroxy-3,6-dioxo-2,3,5,6-tetrahydro-1H-
1447

KAYUKOV et al.
1448
carbon atoms of the pyrrole ring: C7a (151.34 ppm), C3a
Scheme 1.
(84.51 ppm), C3 (165.86 ppm), and C1 (92.39 ppm). The
correlation peaks of the amino group signals (7.27 ppm)
and NH of pyridone (11.35 ppm) are not observed likely
due to the broadening of the signals of these groups.
O
NH2
HN
HO
NH
O
In the NOESY spectrum the correlations were
observed corresponding to the coupling between the
protons of the methyl group (1.59 ppm), hydroxy group
(6.47 ppm), and NH of the pyrrole (8.48 ppm) (Fig. 2).
The proton signal of the amino group (7.27 ppm) cor-
relates with the proton signal of the NH of pyridone
(11.35 ppm). Besides the signals of the hydroxy group
protons (1.59 ppm) have two cross-peaks: with the proton
signals of the amino group (7.27 ppm) and with NH of
pyridone (11.35 ppm).
R
O
CN
CN
NC
(1) NaOH
(2) H2SO4
IIа_IIj
R
CN
CN
Iа_Ik
H
CN
NC
O
Na+
NH
O
N
H
III
The spectral data did not permit the unambiguous as-
signment of the positions of the amino and oxo groups
in the pyridine ring, therefore the structure was subjected
to the XRD. Since the obtained crystals of compounds
II were unsuitable for XRD study we prepared to this
end the potassium salt of compound IIa. Potassium salts
of this kind anions as a rule are less soluble in water
and give better crystals than sodium salts. Potassium
4-amino-7-cyano-1-hydroxy-6-oxo-1-phenyl-2,6-dihy-
dro-1H-pyrrolo[3,4-c]pyridin-3-olate (V) was prepared
in two ways: by neutralization of pyrrolopyridine IIa
with potassium carbonate in water and by the direct reac-
tion of tetracyanocyclopropyl ketone Ia with potassium
hydroxide (Scheme 2). In the latter case we observed
that first precipitated potassium 2-benzoyl-1,1,3,3-
tetracyanopropenide (IV), which subsequently slowly
dissolved with the formation of salt V. The structure of
salt V established by XRD analysis confirms the assumed
structure of compounds IIa–IIj. Potassium cation (Fig. 3)
coordinates three anions through the oxygen atoms of the
R = Ph (a), 4-MeOC6H4 (b), 3-NO2C6H4 (c), 4-BrC6H4
(d), 3,4-(MeO)2C6H3 (e), thien-2-yl (f), Me (g), naphth-
1-yl (h), 4-ClC6H4 (i), 2,4-Cl2C6H4 (j), (CH3)3C (k).
pyridines IId, IIg is confirmed by the 13C NMR findings
whose assignment is given in the table and is consistent
with the data for similar compounds [6]. The structure of
pyrrolopyridine IIg was proved by the data of 2D spectra
NOESY and HMBC.
The correlations observed in the HMBC spectrum
correspond to the coupling between the carbon atoms
and protons of the pyrrole ring and its substituents
(Fig. 1). The signals of the protons of the hydroxy group
(6.47 ppm) have three cross-peaks: with the carbon atom
of the methyl group (24.52 ppm) and atoms C1 and C7a
of the pyrrole ring (92.39 and 151.34 ppm). The proton
signals of the methyl group (1.59 ppm) have two cross-
peaks, with C1 and C7a. The proton attached to the nitro-
gen of the pyrrole ring (8.87 ppm) has cross-peaks with all
CH3
CH3
NH
HO
NH
HO
NC
O
O
NC
O
O
N
NH2
N
NH2
H
H
Fig. 1. Spin-spin coupling between the protons of substituents
at the pyrrole ring with carbon atoms according to the 1H-13C
HMCC NMR spectrum of compouns IIg.
Fig. 2. Correlation of protons according to NOESY spectrum
of compound IIg.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

REACTION OF 2,2,3,3-TETRACYANOCYCLOPROPYL KETONES
1449
13C NMR data of compounds IId, IIg, δ, ppm
Scheme 2.
11
10
OH
9 OH
12
Br
OH
9
1
H3C
NH
NH
O
1
NH
3
KOH
13
3
7а
14
O
7а
O
3а
Ia
NC
O
O
3а
NC
NC
CN
K+
NC
8
K+
8
7
7
4
4
6
NH2
N
O
6
CN CN
NH2
N
NH2
N
O
H
H
IV
V
IIg
IId
K2CO3
C1
C3
C3a
C4
C6
C7
C7a
C8
92.08
92.39
165.86
84.51
162.11
168.60
79.19
151.34
115.64
24.52
–
IIa
166.66
86.16
hydroxy and carbonyl groups of the pyrrol fragment and
also through the nitrogen atom of the nitrile function.
Besides in the coordination sphere of potassium cation
four water molecules are present.
162.10
168.04
79.86
151.37
114.68
138.77
128.50
130.98
121.64
The structure of compound III was assumed basing
on the data of IR and 1H, 13C NMR spectra. The 1H NMR
spectrum contains two signals: a singlet at 0.92 ppm
corresponding to tert-butyl substituent, and a slightly
broadened signal at 7.20 ppm, which we assigned to
two NH protons. The 13C NMR spectrum also shows the
symmetry of the molecule.
C9
C10, C14
C11, C13
C12
–
–
We presume that the transformations of tetracyano-
cyclopropyl ketones I under the action of the hydroxide
ion proceed along Scheme 3.
tetracyanopropenide B. This assumption is confirmed
by the possibility to isolate this intermediate in the reac-
tion with potassium hydroxide. The arising propenide
contains two types of electrophilic centers: four cyano
groups conjugated with the propenide skeleton, and a
carbonyl group cross-conjugated with them. We presume
In the first stage in the course of acid-base reaction a
tetracyanocyclopropyl cation A is generated, which suf-
fers an electrocyclic opening giving the corresponding
Fig. 3. Molecular structure and a fragment of crystal lattice of potassium 4-amino-7-cyano-1-hydroxy-3-oxo-1-phenyl-2,6-dihydro-1H-
pyrrolo[3,4-c]pyridin-3-olate (V) according to XRD analysis.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

KAYUKOV et al.
1450
that the reaction follows by adding a hydroxide ion to the
carbonyl group with the subsequent closure of a furan
ring and the formation of intermediate C. Intermediate C
contains a furanimine fragment that due to the presence
of heteroatom with a mobile hydrogen in the geminal
position to the oxygen atom is capable to undergo the
iminolactone-lactam rearrangement with the formation
of pyrrole intermediate D. This type rearrangement was
formerly observed in several cases [10–13]. In the formed
pyrrole intermediate D because of the spatial proximity of
a hydroxyl and a cyano group of the dicyanomethylidene
fragment a heterocyclization is probable with the forma-
tion of furopyrrol intermediate E. In this intermediate the
oxygen atom also has a geminal NH group, therefore the
opening of the furan ring becomes possible. The forming
in this process intermediate F undergoes the cyclization
giving a pyridine ring. The neutralization of the reaction
mixture leads to the formation of final products II. The
alternative mechanism involving the primary attack of
the hydroxide ion on the cyano groups cannot explain the
reaction regioselectivity and disagrees with the results of
the analogous reaction of 2-aroyltetracyanopropenides
with alcoholate and oximate ions which due to the impos-
sibility of the iminolactone-lactam rearrangement stops at
the stage of the formation of dihydrofurans corresponding
to intermediate C [14].
The abnormal result of the reaction between the hy-
droxide ion and cyclopropyl ketone Ik may be ascribed to
the steric effect of the tert-butyl group. It is reasonable to
assume that the initial course of the reaction is the same
as with the other tetracyanocyclopropyl ketones till the
formation of intermediate F [R = (CH3)3C] (Scheme 4).
In intermediate F two heterocyclization possibilities exist
involving the carboxamide group: the cyclization with
Scheme 3.
O
NC
NC
NC
CN
CN
CN
CN
CN
CN
_
OH _
_H2O
O
R
HO
O
R
R
OH
Iа_Ij
CN
CN
NC
B
А
NH
N
NH
H OH
CN
O
O
O
CN
CN
CN
H2O
_OH _
HO
HO
HO
H O
R
R
R
CN
CN
O
NC
NC
NC
C
NH2
O
O
O
HN
N
HN
CN
CN
CN
CN
CN
O
O
R
HO
R
_H2O
NH2
R
R
CN
CN
O
NC
NC
NC
NH
D
E
F
O
O
NH
NH
HN
HO
N
H2SO4
_HSO4
H2O
IIа_IIj
NH
O
NH
O
R
R
NC
NC
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

REACTION OF 2,2,3,3-TETRACYANOCYCLOPROPYL KETONES
1451
the participation of a cyano group with the formation
of the pyrrolopyridine system realized in the case of the
most cyclopropyl ketones, and the second way leading
to a pyrrolpyrrole system. The formation of the pyridine
ring should occur in the conformation where the cyano
group should be in the same plane as the hydrocarbon
substituent, and this position creates steric hindrances in
the case of a bulky substituent like the tert-butyl group.
In the pyrrolpyrrole derivative the steric hindrances in-
significantly differ from those in intermediate E, for the
place of the oxygen atom at the sp3-hybridized carbon is
occupied by the NH moiety of the pyrrol ring.
group should result in another course of the reaction.
Actually, in the reaction of 3-benzoyl-3-methylcyclopro-
pane-1,1,2,2-tetracarbonitrile (Il) with water solution of
sodium hydroxide the three-membered ring is conserved,
and transformations occur at the functional groups.After
the acidifying of the reaction mixture with 5% solution
of sulfuric acid we isolated in 74% yield 11-methyl-4-
phenyl-3,5,9-triazatetracyclo-[5.3.1.01,7.04,11]undecane-
2,6,8,10-tetraone (VI) (Scheme 5).
The structure of tetracycle VI was established by
XRD analysis. The molecular structure and a fragment of
crystal packing are shown on Fig. 4. All hydrogen atoms
bound to atoms N1, N2, N3take part in hydrogen bonds
N1–H1⋯O1i, N2–H2⋯O1iii, N3–H3⋯O2ii. As a result the
molecules form chains directed along the crystallographic
axis c. Among the features of the molecular structure the
Since the first stage in the reactions of cyclopropanes
Ia–Ik with the solution of sodium hydroxide is the proton
abstraction with the subsequent ring opening, it is expect-
able that the replacement of the hydrogen by a methyl
Scheme 4.
O
NC
NC
O
CN
CN
N
CN
CN
CN
CN
NaOH
III
CN
CN
O
H
H2N
O
Scheme 5.
NH
O
H
O
NC
O OH
Ph
N
O O
Ph
O
CN
CN
OH_
CN
CN
Ph
H3C
CN
CN
CN
CN
Ph
CN
H3C
H3C
H3C
NC
Il
NC
NC
NC
OH
O
O
O
O
O
HN
HN
CN
CN
HN
CN
CN
N
H2O
Ph
Ph
_OH _
Ph
H3C
H3C
HN
H3C
CN
O
HN
NH
O
O
O
O
O
O
HN
HN
HN
N_
NH
H2O
_NH3
H+
Ph
NH
N
Ph
Ph
H3C
HN
H3C
HN
H3C
HN
O
O
O
O
VI
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

KAYUKOV et al.
1452
Fig. 4. Molecular structure and a fragment of the crystal lattice of the complex of 11-methyl-4-phenyl-3,5,9-triazatetracyclo[5.3.1.01,7.04,11]-
undecane-2,6,8,10-tetraone (VI) with dimethyl sulfoxide according to XRD data. The atoms numeration obeys the rules common for
XRD analysis.
form of the three-membered ring like isosceles triangle
should be mentioned: the bonds C4–C5 (1.501 Å) and C3–
C5 [1.504(3) Å] are shorter than the bond C3–C4 [1.553(3)
Å]. The C11–O2 bond of the carbonyl group whose oxygen
is involved in the hydrogen bond formation is somewhat
extended compared with the other carbonyl groups. The
other bond lengths and bond angles are of usual values
and do not require a detailed description.
before. The formation of tetracycle VI may be described
by an alternative scheme where the transformations in-
volving the carbonyl group start with the addition of the
hydroxide ion to cyano groups. In order to prove that the
reaction proceeded through the furan ring formation we
investigated the reaction of cyclopropane Il with methanol
in the presence of sodium methylate.
It was established using the data of mass,
1H NMR, and IR spectra that in this reaction formed
6-amino-1-imino-3,4,4-trimethoxy-3a-methyl-3-phenyl-
3,3a,3b,4-tetrahydro-1H-furo[3’,4’:1,3]cyclo-propa[1,2-
c]pyrrol-3b-carbonitrile (VII) (Scheme 6). The involve-
ment of the carbonyl group in this process is confirmed by
the upfild shift of the ortho-proton signals of the phenyl
substituent [8.02 ppm (Il), 7.48 ppm (VII)]. The presence
of an imine fragment was confirmed by the presence in the
IR spectrum of a narrow band at 3382 cm–1 and a singlet
The reactions of alkyltetracyanocyclopropanes with
sodium hydroxide are known where all cyano groups are
involved resulting in (1S*,5S*)-5-carbamoyl-2,4-dioxo-
3-azabicyclo[3.1.0]hexane-1-carboxylic acids [15, 16].
An essential distinction of cyclopropane Il is the presence
of a carbonyl group taking part in the reaction. Therewith
it is most probable that the transformations start with the
addition of a hydroxide ion to the carbonyl group with
subsequent cyclization-recyclization processes involving
the spatially close cyano groups. The formed intermedi-
ate furanimine derivatives undergo recyclization into
pyrrole structures, and it occurs twice involving both
cyano groups located in the cis-position with respect
to the carbonyl. Similar processes were observed in the
reaction of cyclopropane Il with water [17]. The reaction
of the trans-cyano groups with the hydroxide ion prob-
ably occurs independently and results in the formation
of a pyrrole ring. On the whole the reaction results in the
formation of a polyheterocyclic structure containing a
three-membered carbocycle fused with pyrrole rings. No
compounds with this heterocyclic system were described
1
at 8.33 ppm in the H NMR spectrum. The addition of
methanol to cyano groups located in the trans-position
Scheme 6.
H3CO
NH
O
NH2
CH3OH, CH3ONa
Il
N
H3C
OCH3
OCH3
NC
VII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

REACTION OF 2,2,3,3-TETRACYANOCYCLOPROPYL KETONES
1453
with respect to benzoyl leads to the formation of the
pyrrole ring. On the other hand, the methanol attack is
directed on the carbonyl group and results in the formation
of iminolactone fragment which does not rearrange into
the lactam due to the lack of proton-generating substituent
in the β-position to the oxygen atom of the furan ring.
of 7% NaOH solution and left standing for 24 h. Then
the reaction mixture was neutralized with 10% solution
of H2SO4, the separated precipitate was filtered off and
washed with water. Yield 0.26 g (87%), mp 145–147°C
(decomp.).
Compounds IIb–IIj were obtained similarly by proce-
dure a. 4-Amino-1-hydroxy-1-(4-methoxyphenyl)-3,6-
dioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-
carbonitrile (IIb). Yield 73%, mp 142–144°C (decomp.)
{142–144°C (decomp.) [9]}.
EXPERIMENTAL
Monitoring the reaction progress and checking the
purity of compounds was carried out by TLC on Silufol
UV-254 plated (spots visualizing by UV irradiation,
iodine vapor, or thermal degradation). IR spectra were
taken from thin films (mulls in mineral oil) on a Fourier
spectrophotometer FSM-1202. 1H and 13C NMR spectra
were registered on a spectrometer Bruker DRX-500 at op-
erating frequencies 500.13 and 125 MHz from solutions
in DMSO-d6, internal reference TMS. Mass spectra were
measured on an instrument Finnigan MAT INCOS 50 (EI,
energy of ionizing electrons 70 eV). Elemental analysis
was performed on an instrument Laboratorni Přistroje,
Praha. The X-ray diffraction study of single crystals V, VI
was carried out on a four-circle automatic diffractometer
CAD-4 Enraf Nonius, CuKα-radiation, graphite mono-
chromator, ω-scanning. The structures were solved by the
direct method using SHELXS-97 software.The refining of
positions and thermal parameters of nonhydrogen atoms
was performed in full-matrix anisotropic approximation.
The positions of hydrogen atoms were found from the
difference Fourier syntheses and freely refined in the
isotropic approximation for compound V. The positions
of hydrogen atoms in structure VI were calculated and
refined in the rider model.
4-Amino-1-hydroxy-1-(3-nitrophenyl)-3,6-dioxo-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-
carbonitrile (IIc). Yield 70%, mp 183–184°C (decomp.)
{mp 183–184°C (decomp.) [9]}.
4-Amino-1-(4'-bromophenyl)-1-hydroxy-3,6-
dioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-
7-carbonitrile (IId). Yield 70%, mp 136–140°C (de-
comp.). IR spectrum, ν, cm–1: 3285, 3232 (NH2), 2219
(C≡N), 1716, 1698 (C=O). 1H NMR spectrum, δ, ppm:
7.10–7.60 br.s (2H, NH2), 7.33 s (1H, OH), 7.40 d (2Harom
,
J 8.5 Hz), 7.51 d (2Harom, J 8.5 Hz), 8.90 s (1H, NH),
11.41 s (1H, NH). Mass spectrum, m/z (Irel, %): 362 (1),
360 (1) [M]+, 344 (8), 342 (8) [M – 18]+, 187 (5), 161
(31), 157 (7), 155 (7) [C6H4Br]+, 133 (100). Found, %:
C 46.61; H 2.53; N 15.43. C14H9BrN4O3. Calculated, %:
C 46.56; H 2.51; N 15.51. M 359.99.
4-Amino-1-(3',4'-dimethoxyphenyl)-1-hydroxy-
3,6-dioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyr-
idine-7-carbonitrile (IIe). Yield 69%, mp 132–134°C
(decomp.). IR spectrum, ν, cm–1: 3275, 3221 (NH2), 2220
(C≡N), 1714, 1687 (C=O). 1H NMR spectrum, δ, ppm:
3.745 s (3H, CH3), 3.75 s (3H, CH3), 6.86 d.d (1Harom
,
3J 8.4, 4J 2.0 Hz), 6.92 d (1Harom, 3J 8.5 Hz), 7.19 s (1H,
The crystallographic data are deposited in the Cam-
bridge Crystallographic Data Center [CCDC no. 851386
(V), 851385 (VI)] and can be obtained free by e-mail:
deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk.
4
OH), 7.23 d (1Harom, J 2.1 Hz), 7.38 br.s (2H, NH2),
8.83 s (1H, NH), 11.41 s (1H, NH). Found, %: C 56.15;
H 4.14; N 16.33. C16H14N4O5. Calculated, %: C 56.14;
H 4.12; N 16.37.
4-Amino-1-hydroxy-3,6-dioxo-1-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(IIa). a. In 15 ml of 7% NaOH solution was dissolved
at stirring 2.46 g (0.01 mol) of 2,2,3,3-tetracyanocyclo-
propyl ketone Ia, and the mixture was left standing for
24 h. Then the reaction mixture was neutralized with
10% solution of H2SO4, the separated precipitate was
filtered off and washed with water. Yield 1.89 g (67%),
mp 145–147°C (decomp.) {145–147°C (decomp.) [9]}.
4-Amino-1-hydroxy-3,6-dioxo-1-(thien-2-yl)-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-car-
bonitrile (IIf). Yield 70%, mp 165–166°C (decomp.).
IR spectrum, ν, cm–1: 3289, 3218 (NH2), 2226 (C≡N),
1718, 1696 (C=O). 1H NMR spectrum, δ, ppm: 7.01 d.d
(1H, C4H3S, J 5.0, J 3.6 Hz), 7.10 d.d (1H, C4H3S,
3J 3.6, 4J 1.2 Hz), 7.35 br.s (2H, NH2), 7.43 s (1H, OH),
7.50 d.d (1H, C4H3S, 3J 5.0, 4J 1.4 Hz), 9.05 s (1H, NH),
11.41 s (1H, NH). Found, %: C 50.05; H 2.86; N 19.39.
C12H8N4O3S. Calculated, %: C 50.00; H 2.80; N 19.43.
3
3
b. 0.27 g (0.001 mol) of sodium 1,1,3,3-tetracyano-
2-benzoylpropenide was dissolved at stirring in 3 ml
4-Amino-1-hydroxy-1-methyl-3,6-dioxo-2,3,5,6-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

KAYUKOV et al.
1454
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(IIg). Yield 69%, mp 132–134°C (decomp.). IR spectrum,
ν, cm–1: 3271, 3212 (NH2), 2224 (C≡N), 1707, 1689
a precipitate formed. The separated precipitate was fil-
tered off, washed with 5% solution of H2SO4 and with
water. Yield 2.45 g (92%), mp 164–165°C (decomp.). IR
spectrum, ν, cm–1: 3358 (NH), 2209 (C≡N), 1673 (C=O).
1H NMR spectrum, δ, ppm: 0.91 s [9H, C(CH3)3], 7.20 s
(2H, NH). 13C NMR spectrum, δ, ppm: 24.66 [C(CH3)3],
41.73 [C(CH3)3], 72.40 (C6a), 83.96 (C3,4), 117.75 (CN),
174.13 (C2,5), 176.13 (C3a). Found, %: C 54.05; H 4.35;
N 20.98. C12H11N4NaO2. Calculated, %: C 54.14; H 4.16;
N 21.04.
1
(C=O). H NMR spectrum, δ, ppm: 1.60 s (3H, CH3),
6.50 s (1H, OH), 7.34 br.s (2H, NH2), 8.51 s (1H, NH),
11.42 s (1H, NH). Mass spectrum, m/z (Irel, %): 205 (5)
[M – 15]+, 202 (24) [M – 18]+, 187 (3). Found, %: C 49.17;
H 3.72; N 25.43. C9H8N4O3. Calculated, %: C 49.09;
H 3.66; N 25.45. M 220.18.
4-Amino-1-hydroxy-1-(naphth-1-yl)-3,6-dioxo-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-car-
bonitrile (IIh). Yield 61%, mp 121–125°C (decomp.). IR
spectrum, ν, cm–1: 3282, 3224 (NH2), 2230 (C≡N), 1705,
1690 (C=O). 1H NMR spectrum, δ, ppm: 7.25–7.75 br.s
(2H, NH2), 7.32 s (1H, OH), 7.42–7.55 m (5Harom),
7.94–7.98 m (2Harom), 9.01 s (1H, NH), 11.49 s (1H,
NH). Mass spectrum, m/z (Irel, %): 314 (12) [M – 18]+,
127 (6), 126 (6). Found, %: C 65.27; H 3.62; N 16.43.
C18H12N4O3. Calculated, %: C 65.06; H 3.64; N 16.86.
M 332.09.
b. The compound was obtained analogously from
2-pivaloyl-1,1,3,3-tetracyanopropenide. Yield 2.50 g
(94%).
Potassium 2-benzoyl-1,1,3,3-tetracyanopropenide
(IV).Amixture of 0.25 g (0.001 mol) of cyclopropane Ia
and 0.06 g (0.001 mol) of potassium hydroxide in 3 ml of
water was stirred for 10 min; therewith the reagent first
completely dissolved and later a precipitate formed. The
separated precipitate was filtered off, and washed with
water. Yield 0.18 g (64%), mp 230–231°C (decomp.). IR
spectrum, ν, cm–1: 2202 (C≡N), 1657 (C=O).
4-Amino-1-hydroxy-1-(4-chlorophenyl)-3,6-dioxo-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-car-
bonitrile (IIi). Yield 77%, mp 146–148°C (decomp.). IR
spectrum, ν, cm–1: 3285, 3230 (NH2), 2225 (C≡N), 1709,
1685 (C=O). 1H NMR spectrum, δ, ppm: 7.10–7.60 br.s
(2H, NH2), 7.33 (1H, OH), 7.42–7.48 m (AA'BB' sys-
tem, 4Harom), 8.90 s (1H, NH), 11.41 s (1H, NH). Mass
spectrum, m/z (Irel, %): 300 (3), 298 (10) [M – 18]+, 187
(7), 161 (38), 133 (100). Found, %: C 52.87; H 2.92;
N 17.43. C14H9ClN4O3. Calculated, %: C 53.09; H 2.86;
N 17.69. M 316.04.
Potassium 4-amino-7-cyano-1-hydroxy-6-oxo-1-
phenyl-2,6-dihydro-1H-pyrrolo[3,4-c]pyridine-3-olate
(V). a. To 3 ml of 5% solution of potassium hydroxide
was added 0.28 g (0.001 mol) of potassium tetracyano-
propenide IV, and the mixture was stirred till complete
dissolution of the reagent. The solution was evaporated.
The separated precipitate was filtered off, and washed
with a saturated solution of potassium chloride. Yield
0.14 g (45%), mp 112–115°C (decomp.). IR spectrum,
ν, cm–1: 3362 (NH), 2209 (C≡N), 1675 (C=O). Found, %:
C 52.45; H 2.85; N 17.48. C14H9KN4O3. Calculated, %:
C 52.49; H 2.83; N 17.49.
4-Amino-1-hydroxy-1-(2,4-dichlorophenyl)-3,6-
dioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-
7-carbonitrile (IIj). Yield 56%, mp 137–141°C (de-
comp.). IR spectrum, ν, cm–1: 3272, 3222 (NH2), 2225
(C≡N), 1711, 1670 (C=O). 1H NMR spectrum, δ, ppm:
7.10–7.60 br.s (2H, NH2), 7.48 s (1H, OH), 7.52 d.d
b. To a solution of 0.07 g (0.0005 mol) of K2CO3 in
5 ml of water was added 0.28 g (0.001 mol) of pyrrolo-
pyridine IIa, the solution obtained was evaporated. The
separated precipitate was filtered off, and washed with
a saturated solution of potassium chloride. Yield 0.18 g
(56%).
3
4
4
(1Harom, J 8.6, J 2.0 Hz), 7.56 d (1Harom, J 2.0 Hz),
8.11 d (1Harom, 3J 8.6 Hz), 8.78 s (1H, NH), 11.42 s (1H,
NH). Mass spectrum, m/z (Irel, %): 334 (0.3), 332 (1) [M
– 18]+, 161 (29), 133 (69). Found, %: C 47.77; H 2. 32;
N 15.73. C14H8Cl2N4O3. Calculated, %: C 47.89; H 2.30;
N 15.96. M 350.00.
The molecule of compound V crystallized with
two water molecules. C14H9KN4O3·2H2O. M 356.38;
a = b = 25.595(3), c 9.0761(18) Å; V 5945.6(4) Å3;
dcalc 1.593 g/cm3; space group I41/a, Z 16; R 0.055.
Sodium 6a-tert-butyl-3,4-dicyano-5-oxo-1,5,6,6a-
tetrahydropyrrolo[2,3-b]pyrrol-2-olate (III). a.Amix-
ture of 2.26 g (0.01 mol) of cyclopropane Ik with 15 ml of
5% solution of sodium hydroxide was stirred for 10 min;
therewith the reagent first completely dissolved and later
11-Methyl-4-phenyl-3,5,9-triazatetracyc-
lo[5.3.1.01.7.04.11]undecane-2,6,8,10-tetraone (VI).
To 10 ml of 5% solution of NaOH was added 2.60 g
(0.01 mol) of cyclopropane Il, and the mixture was stirred
till complete dissolution of the reagent. After standing
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

REACTION OF 2,2,3,3-TETRACYANOCYCLOPROPYL KETONES
1455
Makovec, F., Doucet, E., Hamon, M., Menziani, M.C.,
De Benedetti, P.G., Giorgi, G., Ghelardini, C., and Col-
lina, S., Bioorg. Med. Chem., 2002, vol. 10, p. 779.
2. Kravchenko, D.V., Kuzovkova, Y.A., Kysil, V.M.,
Tkachenko, S.E., Maliarchouk, S., Okun, I.M., Bala-
kin, K.V., Ivachtchenko,A.V. J. Med. Chem., 2005, vol. 48,
p. 3680.
3. Kosulina, T.P., Kaigorodova, E.A., Kul’nevich, V.S.,
Sapunov, A.Ya., Govorova, S.A. Khim.-Farm. Zh., 1997,
vol. 31, p. 30.
for 10 h the reaction mixture was neutralized with 5%
solution of H2SO4. The separated precipitate was filtered
off, and washed with water. Yield 2.32 g (78%), mp
227–228°C (decomp.). IR spectrum, ν, cm–1: 3428 (NH),
1
1710 (C=O). H NMR spectrum, δ, ppm: 0.98 s (3H,
CH3), 7.49–7.53 m (3Harom), 7.56 d (2Harom, 3J 7.3 Hz),
9.08 s (2H, NH), 11.59 s (1H, NH). Found, %: C 60.88;
H 3.86; N 14.10. C15H11N3O4. Calculated, %: C 60.61;
H 3.73; N 14.14.
4. Delaine, T., Bernardes-Génisson, V., Meunier, B., Berna-
dou, J. J. Org. Chem., 2007, vol. 72, p. 675.
5. Delaine, T., Bernardes-Génisson, V., Stigliani, J., Gor-
nitzka, H., Meunier, B., Bernadou, J. Eur. J. Org. Chem.,
2007, p. 1624.
6. Delaine, T., Bernardes-Génisson, V., Quémard, A., Con-
stant, P., Meunier, B., Bernadou, J. Eur. J. Med. Chem.,
2010, vol. 45, p. 4554.
The molecule of compound VI crystallized with
a molecule of dimethyl sulfoxide. C15H11N3O4·SO(CH3)2,
M 375.4. a 7.879(1), b 14.75(2), c 15.089(2) Å,
V 1709.0(4) Å3. Space group P212121, Z 4, dcalc 1.459,
R 0.049.
6-Amino-1-imino-3,4,4-trimethoxy-3a-methyl-
3-phenyl-3,3a,3b,4-tetrahydro-1H-furo[3',4':1,3]-
cyclopropa[1,2-c]pyrrol-3b-carbonitrile (VII). In 10 ml
of methanol was dissolved 0.046 g (2 mmol) of sodium
metal. The solution obtained was added at stirring to
a slurry of 2.60 g (0.01 mol) of cyclopropane Il in 10 ml
of methanol. After 5 h the separated precipitate was fil-
tered off and washed with methanol. Yield 2.57 g (72%),
mp 216–217°C (decomp.). IR spectrum, ν, cm–1: 3382
(NH), 3265, 3193 (NH2), 2255 (C≡N), 1712 (C=NH).
1H NMR spectrum, δ, ppm: 0.76 s (3H, CH3), 3.15 s (3H,
7. Broussy, S., Bernardes-Génisson, V., Quémard,A., Meuni-
er, B., Bernadou, J. J. Org. Chem., 2005, vol. 70, 10502.
8. Broussy, S., Bernardes-Génisson, V., Coppel, Y.,
Quémard, A., Meunier, B., Bernadou, J., and Meuni-
era, B., Org. Biomol. Chem., 2005, vol. 3, p. 670.
9. Kayukov, Ya.S., Bardasov, I.N., Kayukova, O.V., Er-
shov, O.V., Nasakin, O.E., Zh. Org. Khim., 2010, vol. 46,
p. 1263.
10. Ershov, O.V., Lipin, K.V., Eremkin, A.V., Kayukov, Ya.S.,
Nasakin, O.E., Zh. Org. Khim., 2009, vol. 45, p. 479.
11. Sheverdov, V.P., Ershov, O.V., Nasakin, O.E.,
Chernushkin, A.N., Tafeenko, V.A., Firgang, S.I.
Tetrahedron., 2001, vol. 57, p. 5815.
12. Nasakin, O.E., Sheverdov, V.P., Ershov, O.V.,
Moiseeva, I.V., Lyshchikov, A.N., Khrustalev, V.N.,
Antipin, M.Ju. Mendeleev, Commun., 1997, vol. 3, p. 112.
13. Ershov, O.V., Sheverdov, V.P., Nasakin, O.E.,
Tafeenko, V.A., Zh. Org. Khim., 2001, vol. 37, p. 1732.
14. Bardasov, I.N., Kayukova, O.V., Kayukov, Ya.S.,
Ershov, O.V., Nasakin, O.E., Tafeenko, V.A., Zh. Org.
Khim., 2009, vol. 45, p. 1340.
OCH3), 3.25 s (3H, OCH3), 3.83 s (3H, OCH3), 6.75 br.s
3
(2H, NH2), 7.38 t (1Harom, J 7.2 Hz), 7.44 t (2Harom
,
3J 7.2 Hz), 7.48 d (2Harom, 3J 7.1 Hz), 8.32 s (1H, NH).
Mass spectrum, m/z (Irel, %): 356 (1) [M]+. Found, %:
C 60.86; H 5.72; N 15.56. C18H20N4O4. Calculated, %:
C 60.66; H 5.66; N 15.72. M 356.15.
ACKNOWLEDGMENTS
The study was performed in the framework of the
Federal target program “Scientific and scientific-peda-
gogical staff of the innovative Russia” (State contract
no. 16.740.11.0335).
15. Hart, H., Freeman, F. J. Am. Chem. Soc., 1963, vol. 85,
p. 1161.
16. Hart, H., Freeman, F. J. Org. Chem., 1963, vol. 28, p. 2063.
17. Kayukov, Ya.S., Bardasov, I.N., Ershov, O.V., Nasa-
kin, O.E., Kayukova, O.V., Tafeenko, V.A., Zh. Org. Khim.,
2012, vol. 48, p. 487.
REFERENCES
1. Cappelli, A., Anzini, M., Vomero, S., Mennuni, L.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012