Studies on the reaction of cycloalkanones with malonodinitrile

Article abstract of DOI:10.1002/jhet.1883

Cyclopentanone reacts with malononitrile catalyzed by piperidine or sodium acetate to afford under any case cyclopentylidenemalononitrile dimer: 5-aminospiro-[2,6,7,7a-tetrahydroindene-7,1′-cyclopentane]-4,6,6-tricarbonitrile (7) as the sole product. Contrary to this behavior, cyclohexanone reacts with malononitrile catalyzed by piperidine to afford the analogous cyclohexylidenemalononitrile dimer: 2-aminospiro-[3,4,5,6,7,4a-hexahydronaphthalene-4,1′-cyclohexane]-1,3,3-tricarbonitrile (11); whereas when the reaction is catalyzed by sodium acetate, it afforded 9,10-diaza-8,11-dioxo-tricyclo-[4.3.3.0^1,6]-dodecane-7,12-dicarbonitrile (12). The structures of these products were established on the basis of their elemental analysis and spectral data, and plausible mechanism has been postulated to account for their formation. X-ray crystallography was carried out as a further evidence for structures 7 and 12.

Full text of DOI:10.1002/jhet.1883

Month 2014
Studies on the Reaction of Cycloalkanones with Malonodinitrile
a
a
a
Fathy M. Abdelrazek, Nadia H. Metwally, Nazmi A. Kassab, Mohammed T. Jaafar,a† Peter Metz,b and Anne Jägerb
*
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
bInstitute of Organic Chemistry, Technical University of Dresden, 01069 Dresden, Germany
*
E-mail: prof.fmarzek@gmail.com
†This work is abstracted in part from the M.Sc. thesis of Mr. Mohamed T. Jaafar.
Received August 12, 2012
DOI 10.1002/jhet.1883
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
CN
EtOH/NaOAc; r.t.
O
O
CN
4
O
3
EtOH/Piperidine
, r.t.
EtOH/Piperidine
or EtOH/NaOAc; r.t.
8
8
O
CN
NH2
NC
NC
NC
CN
NH
NH
CN
CN
NH2
CN
O
12
11
7
Cyclopentanone reacts with malononitrile catalyzed by piperidine or sodium acetate to afford under any
case cyclopentylidenemalononitrile dimer: 5-aminospiro-[2,6,7,7a-tetrahydroindene-7,10-cyclopentane]-
4,6,6-tricarbonitrile (7) as the sole product. Contrary to this behavior, cyclohexanone reacts with malononitrile
catalyzed by piperidine to afford the analogous cyclohexylidenemalononitrile dimer: 2-aminospiro-
[3,4,5,6,7,4a-hexahydronaphthalene-4,10-cyclohexane]-1,3,3-tricarbonitrile (11); whereas when the reaction is
catalyzed by sodium acetate, it afforded 9,10-diaza-8,11-dioxo-tricyclo-[4.3.3.01,6]-dodecane-7,12-dicarbonitrile
(12). The structures of these products were established on the basis of their elemental analysis and spectral data,
and plausible mechanism has been postulated to account for their formation. X-ray crystallography was carried
out as a further evidence for structures 7 and 12.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
Pyridines and pyrido-fused derivatives are important
heterocyclic compounds that find many pharmaceutical
and agrochemical applications [1–5]. In the last two
decades, we have been involved in a program aiming to
develop new simple routes for the synthesis of heterocyclic
compounds of biological interest [6–13]. In the context of
this program, we have reported that 2-(1-arylehtylidene)
malononitrile (1) undergoes dimerization upon reflux in
ethanolic sodium ethoxide to afford 2-(3-cyano-6-methyl-
4,6-diaryl-5,6-dihydro-1H-pyridin-2-ylidene)-malononitrile
(2) (Scheme 1), and its structure was proven through X-ray
crystallographic analysis, and a plausible mechanism was
suggested for this transformation [14,15].
For this purpose, cyclopentylidenemalononitrile (5)
was needed (Scheme 2). This compound was reported to
be obtained via Knoevenagel condensation between
cyclopentanone (3) and malononitrile (4) in the presence
of sodium acetate at RT, as yellow crystals of mp
83–85ꢀC [16,17].
In our hands, the reaction of cyclopentanone (3) with
malononitrile (4) in ethanol catalyzed by sodium acetate
or piperidine at RT has afforded colorless crystalline
product with mp 195ꢀC. The mass spectrum of this
product revealed a base peak at m/z = 264 that is twice
of the molecular weight of 5 (m/z = 132) (Scheme 2);
denoting a dimer of 5. The IR spectrum of this product
showed absorption band at nmax = 3404, 3326, and
2221 cmꢁ1 attributable to amino and cyano groups, respec-
It seemed interesting to investigate the reaction of
cycloalkylidenes of malononitrile (having methylene
group instead of CH3; neighboring the C═C) with sodium
ethoxide and see if a dimer of similar structure will be
obtained (Fig. 1).
1
tively. The H-NMR spectrum of this product revealed a
multiplet at d = 1.34–2.40ppm integrated for 12 protons
and a triplet at d = 3.0 ppm integrated for 1H and a triplet
© 2014 HeteroCorporation

F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, M. T. Jaafar, P. Metz, and A. Jäger
Vol 000
Scheme 1. Dimerization of 2(1-arylethylidene)-malononitrile.
in situ undergoes proton elimination to afford A that
undergoes electron shift to give the keneteneimine B.
This latter undergoes electrocyclic addition to another
molecule of 5 to afford C that gains a proton to give the
imine D. The imine D then undergoes a 1,5-H shift to
afford our product 7 (Scheme 3) [20].
Ar
NC
Ar
Ar
CH3
NaOEt
CN
CN
NC
NC
H3C
N
H
On the other hand, we have prepared cyclopentylidene-
malononitrile (5) via the condensation of 3 and 4 according
to literature method [21]. Leaving compound 5 in ethanol
with piperidine or sodium acetate as catalyst at RT overnight,
we could obtain the same dimer 7 as shown by the melting
points and TLC analysis.
1
2
n
n= 1, 2
NC
NC
It seemed interesting to investigate the reaction of
cyclohexanone (8) with malononitrile (4) under the same
reaction conditions to see if the condensation product 9
or our expected dimer 10 (Fig. 1; n = 2) or an analogous
dimer (structure 11; Scheme 4) will be obtained. However,
in contrast to the behavior of cyclopentanone (3) with
malononitrile (4), the product of the reaction of cyclohexa-
none (8) with malononitrile (4) was found to depend on
the catalyst used. Thus, cyclohexanone (8) reacts with 4 in
ethanol at RT catalyzed by piperidine to afford a yellow
crystalline product of mp 173ꢀC. The mass spectrum of this
product revealed a base peak at m/z = 292 that corresponds
to a dimer of cyclohexylidenemalononitrile (9) (m/z = 146).
Two possible structures can be assumed for this dimer: either
our initially expected dimer 10 (Fig. 1, n = 2) or structure 11
n
NC
N
H
Figure 1. The structure of the initially expected dimers.
at d = 5.50 ppm assignable to an olefinic proton in
addition to a D2O-exchangeable signal (2H) appeared at
d = 7.52 ppm.
These spectral data are not applicable completely to our
expected dimer structure 6 shown in Scheme 2; Figure 1
(n = 1). Therefore, an X-ray crystallography [18,19]
seemed necessary to verify the actual structure of this
dimer for which structure 7 was assigned (Fig. 2).
A plausible mechanism for the formation of this cyclo-
pentylidenemalononitrile dimer is outlined in Scheme 3
and involves the initial Knoevenagel condensation of
cyclopentanone (3) with malononitrile (4) to afford 5 that
1
(analogous to the dimer 7). The IR and H-NMR spectra
of this product were in complete agreement with struc-
ture 11 that was assigned for this dimer (cf. Experimental;
Scheme 4). The reaction of cyclohexanone (8) with malono-
nitrile (4) in ethanol catalyzed by piperidine to afford the
Scheme 2. The reaction of cyclopentanone with malononitrile.
CN
CN
+
O
3
4
EtOH/NaOAc
or EtOH/ Pip., r.t.
NC
CN
NH2
CN
NC
NC
NC
NC
N
CN
H
7
6
5
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DOI 10.1002/jhet

Month 2014
Reaction of Cycloalkanones with Malonodinitrile
Figure 2. X-ray crystallography of compound 7 [18,19].
Scheme 3. Mechanism for the formation of the dimer 7.
_
N
N
CN
CN
NC
NC
CN
CN
CN
NaOAc
_
+
O
CN
4
3
5
A
B
5
H
NC
CN
CN
CN
_
NH2
N
NH
+
Tautomer.
H
CN
CN
CN
CN
CN
C
D
7
dimer 11 apparently followed the same route analogous to
the formation of the dimer 7 as depicted in Scheme 3.
When the reaction of 8 with 4 was carried out in ethanol
in the presence of sodium acetate at RT, a white crystalline
product of mp 289ꢀC was obtained (Scheme 4). The IR
spectrum of this last product showed absorption bands at
signal (1H) at d = 4.57 ppm integrated to one CH proton
and another singlet at 4.80 ppm (1H). In addition, a
D2O-exchangeable signal appeared at d = 9.20 ppm. The
mass spectrum of this product revealed a base peak at
m/z = 244. This mass value as well as the spectral data
(cf. Experimental) are not applicable to either the conden-
sation product 9 (MW 146) or to our expected dimer 10
(Fig. 1; n = 2) (MW 292), or the dimer structure 11 or
any of its tautomers (MW 292). Considering the mass
spectrum and the data of the elemental analysis of
this product, we could calculate a molecular formula
n
max = 3330.5, 3269.7, 2257.3, and 1723 cmꢁ1 presumably
because of NH, CN, and CO groups, respectively. The
1H-NMR spectrum revealed the presence of a multiplet
signals at d = 1.05–2.47 (8H) that can be assigned to the
methylene groups of the cyclohexane ring and a singlet
Journal of Heterocyclic Chemistry
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F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, M. T. Jaafar, P. Metz, and A. Jäger
Vol 000
Scheme 4. The reaction of cyclohexanone with malononitrile.
O
CN
EtOH/Piperidine, r.t.
or EtOH/NaOAc; r.t.
EtOH/NaOAc; r.t.
+
CN
8
4
EtOH/Piperidine, r.t.
O
CN
NC
CN
NH2
NC
NC
NH
NH
NC
CN
CN
NC
NC
N
H
O
12
11
10
9
C12H12N4O2. This formula indicated that one molecule of
cyclohexanone and two molecules of malononitrile are in-
volved in the reaction with one molecule of oxygen and
elimination of one molecule of water. X-ray crystallo-
graphic analysis [23,24] of this product seemed necessary
to verify the correct structure that was shown to be 12 as
depicted in Scheme 4 and Figure 3.
It should be stated that the same compound has been
previously reported as a patent [24] and was obtained in
two steps: from cyclohexan-1,2-dione with cyanoacetamide
in dichloromethane for 9 h to obtain firstly compound 18
(Scheme 5; mp 169ꢀC) and secondly to allow this latter
compound 18 to react with malononitrile in methanol
in the presence of sodium methoxide for 3 h standing at
temperature below 5ꢀC to give 12.
thought to be the spontaneous reaction of oxygen with a
material with readily abstractable hydrogen, for example,
the allylic aero-auto oxidation of limonene to produce
mainly carveol and carvone (Fig. 4) [25–29].
O
OH
Air
+
Catalyst
Carvone
Carveol
R-(+)-Limonene
Figure 4. Auto air oxidation of Limonine.
However, this is the first time this compound is obtained
from cyclohexanone (8) and malononitrile (4). A plausible
mechanism to the formation of this compound from 8 and
4 seemingly involves an autoxidation process. Autoxidation
is a free radical chain process, and free radicals can be
produced purposefully by the decomposition of a radical
initiator, such as benzoyl peroxide. In some cases, initiation
occurs by a process that is not well understood but is
Accordingly, the suggested mechanism as depicted in
Scheme 5 involving firstly the Knövenagel condensation
of 8 and 4 to afford 9a/9b. This latter undergoes allylic
epoxidation to afford 13 that undergoes the small ring
opening to afford 14 that is further autoxidized to afford
15. Water attacks the carbonyl group of 15 with simulta-
neous attack of the resulting OH on one of the cyano
groups to afford the intermediate 16 that in situ undergoes
ring opening to afford the amide 17.
Recyclization of 17 affords the tetrahydroindole deriva-
tive 18 [24]. In our case, compound 18 has not been isolated
but in situ underwent addition of another molecule of 4 to
afford 19 that in its role was cyclized to 20 that undergoes
ring opening to 21 and recyclization to afford 12 as the
isolable product (Scheme 5).
On the other hand, we have prepared cyclohexylidene-
malononitrile (9) via the condensation of 8 and 4 according
to literature method [21].
Leaving cyclohexylidenemalononitrile (9) alone in ethanol
with few drops of piperidine at RT overnight, we obtained
the same dimer 11; whereas leaving an equimolecular
Figure 3. X-ray crystallography of compound 12 [22,23].
Journal of Heterocyclic Chemistry
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Reaction of Cycloalkanones with Malonodinitrile
Scheme 5. Mechanism for the formation of compound 12.
NC
CN
NC
CN
NC
CN
O
NC
CN
OH
O
CN
CN
4
O2/Air
(known
reaction)
epoxidation
8
9a
9b
13
14
O2/ Air
O
O
NC
NH
NC
NC
CN
O
NC
NH2
O
H2O
NH
OH
O
OH
17
18
15
16
CN
CN
O
O
HN
O
NC
NH
NH
NH2
O
NH
NC
NC
NC
NC
NC
NC
NH
OH
N
NC
NC
O
O
O
19
20
21
12
5-Aminospiro-[2,6,7,7a-tetrahydroindene-7,10-cyclopentane]-
mixture of compound 9 and 4 in ethanol with sodium acetate
at RT overnight, we could obtain the same compound 12.
The identity in each case was deduced from matching the
melting points and TLC analysis.
4,6,6-tricarbonitrile (7). Anhydrous sodium acetate (0.01 mol) or
piperidine (1 mL) was added to a mixture of cyclopentanone (3)
(0.01 mol) and malononitrile (4) (0.01 mol) in 50 mL of absolute
ethanol. The reaction mixture was stirred at 25ꢀC for 2 h, diluted
with water, and acidified to pH 3–4 with hydrochloric acid. The
solid so formed was filtered off, washed with water, and crystallized
from dimethylformamide to afford 7 as yellow crystals, yield (60%),
mp 195ꢀC; nmax/cmꢁ1 (KBr) 3404 and 3326 (NH2), 2221 (CN).
dH =1.34–2.40 (m, 12H, 6CH2), 3.0 (t, 1H), 5.50 (t, 1H, ═CH), 7.52
(s, 2H, NH2). MS: m/z = 264. Anal. Calcd for C16H16N4 (264.33): C,
72.70; H, 6.10; N, 21.20. Found: C, 72.50; H, 6.28; N, 21.43%.
As a further proof to this suggested mechanism, cyclohex-
anone (8) was left with malononitrile (4) (1:2) in ethanol and
sodium acetate under argon atmosphere at RT overnight, and
we could only obtain the condensation product 9 in low
yield, whereas the majority of the reactants remained
unreacted, which means that air–oxygen is essential in
the formation of 12. This low yield of the condensation
product can be rationalized on the basis that in the
presence of air–oxygen, the condensation product undergoes
oxidation and thus eliminated from the reaction sphere that
enhances further condensation to take place.
X-ray crystallographic data using Altomare & Mackay [19] program
to solve structure. The X-ray diffraction measurement l = 0.71073 Å;
Crystal data for compound 7; colorless needles C16H16N4 , Mr = 264.332
gꢂ molꢁ1; crystal system, space group: Triclinic, unit cell dimensions:
a= 6.4719(2) Å, b= 8.9917(3) Å, c= 12.0148(4) Å, a = 93.5341(14)ꢀ,
b = 91.8453(13)ꢀ, g = 92.230(2)ꢀ; volume: 696.90(4) Å3; T=298K;
Z= 2; calculated density: 1.260 mg mꢁ3; absorption coefficient: m =0.08
mmꢁ1; reflection 2199 measured, θmax = 27.51ꢀ Rint = 0.019, data
;
EXPERIMENTAL
collection Kappa CCD with graphite monochromator.
2-Aminospiro-[3,4,5,6,7,4a-hexahydronaphthalene-4,10-
Melting points were measured on a digital Electrothermal 9100
apparatus (Kleinfeld, Gehrden, Germany) and are uncorrected.
FTIR spectra (KBr) were obtained on a Nicolet 205 spectropho-
tometer (Nicolet, Madison, WI, USA). 1H-NMR spectra were
obtained on a Bruker AC 300 P- 300 MHz (Bruker, Rheinstetten,
Germany) in DMSO-d6 if not mentioned otherwise. Chemical
shifts are expressed in d values. Mass spectra were recorded
with a Hewlett Packard Esquire-LC (LC/MS; Hewlett Packard,
Palo Alto, CA, USA) at 70 eV. Elemental analyses were carried
out at the Microanalysis Center at Cairo University, Giza,
Egypt. X-ray crystallography of compound 7 was carried out
at National Research Center, Dokki, Giza, Egypt; and X-ray
crystallography of compound 12 was carried out at Technical
University of Dresden, Germany.
cyclohexane]-1,3,3-tricarbonitrile (11).
Piperidine (1 mL)
was added to a mixture of cyclohexanone (8) (0.01 mol) and
malononitrile (4) (0.01 mol) in 50 mL of absolute ethanol. The
reaction mixture was stirred at 25ꢀC for 2 h, then left at RT
overnight, diluted with water, and acidified to pH 3–4 with
hydrochloric acid. The solid so formed was filtered off,
washed with water, and crystallized from dimethylformamide
to afford 11 as pale yellow crystals, yield (61%), mp 173ꢀC.
n
max/cmꢁ1 (KBr): 3438.5 and 3349.7 (NH2), 2214.8 (CN)
cmꢁ1
dH = 1.36–2.05 (m, 17H, cyclohexane + cyclohexene
.
protons), 5.62 (t, 1H, ═CH), 9.20 (s, 2H, NH2). MS: m/z = 292
(25%). Anal. Calcd for C18H20N4 (292.39): C, 73.94; H, 6.89;
N, 19.16. Found: C, 73.90; H, 6.92; N, 19.30.
Journal of Heterocyclic Chemistry
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F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, M. T. Jaafar, P. Metz, and A. Jäger
Vol 000
9,10-Diaza-8,11-dioxo-tricyclo-[4.3.3.01,6]-dodecane-7,12-
dicarbonitrile (12). Anhydrous sodium acetate (0.01 mol)
REFERENCES AND NOTES
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was added to a mixture of cyclohexanone (8) (0.01 mol) and
malononitrile (4) (0.02 mol) in 50 mL of absolute ethanol. The
reaction mixture was stirred at 25ꢀC for 2 h, then left to stand
at RT overnight. To the reaction mixture was added cold
water (10 mL) and neutralized with drops of concentrated HCl
The solid so formed was filtered off, washed with cold water,
and recrystallized from dimethylformamide to afford compound
12 as white crystals, yield (65%), mp 289ꢀC; nmax/cmꢁ1 (KBr)
3330.5 and 3269.7 (NH), 2257.3 (CN), 1723 (CO) cmꢁ1
.
dH = 1.05–2.47 (m, 8H, 4CH2), 4.57 (s, 1H), 4.80 (s, 1H), 9.20
(s, 2H, 2NH).MS: m/z = 244 (26%). Anal. Calcd for C12H12N4O2
(244.25): C, 59.01; H, 4.95; N, 22.94. Found: C, 59.19; H, 4.76;
N, 22.70%.
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X-ray crystallographic data: colorless crystals, C12H12N4O2
(Mr = 244.26g ꢂ molꢁ1), monoclinic, space group P-21/c (No.
14), a = 7.505(1)Ǻ, b = 12.221(4) Ǻ, c = 14.400(1)Ǻ, a[O] = 90.00,
b[O] = 121.60(1), g[O] = 90.00; V[Ǻ3] = 1124.9(4), Z = 4, Dcalcd
=
1.442 g ꢂ cmꢁ3, F(000) = 512 e, m = 0.103mmꢁ1; the final differ-
ence Fourier r = 0.28(ꢁ0.25)e Ǻꢁ3.Crystal dimensions= 0.17
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the Director on application to CCDC, 12 Union Road, Cambridge CB2
IEZ, UK (Fax: +44-01223-336033; e-mail: deposit@ccdc.cam.ac.uk or
www:http://www.ccdc.cam.ac.uk.).
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[22] Crystallographic data (excluding structure factors) for the struc-
ture 12 reported in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication no. CCDC-890175.
Copies of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax.: (internat.)+ 441223/336-
033; e-mail: deposit@ccdc.cam.ac.uk or www:http://www.ccdc.cam.ac.uk.).
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ꢂ 0.13ꢂ 0.09nm. Maximum resolution [sin θ/l] = 0.64 Ǻꢁ1
/
99.9%. Data were collected at T[ꢀC] = ꢁ75(2), with graphite
monochromator with Mo Ka radiation (l = 0.71073 Ǻ) using
the CCD data collection and SADABS absorption correction
method; minimum 98.3%; maximum 99.1%.. Total independent
reflections are 24470 were counted with observed reflections
1840. Rav = 0.051. The final R = 0.045 and R2W = 0.098.
Synthesis of the cycloalkylidene malononitrile derivatives 5
and 9.
Cyclopentylidenemalononitrile (5) and cyclohexy-
lidenemalononitrile (9) were prepared by condensing cyclopentanone
(3) or cyclohexanone (8) with malononitrile (4) according to the
reported literature method [21].
Alternative synthesis of 7 and 11. Piperidine (1 mL) was
added to a solution of either cyclopentylidenemalononitrile (5)
(0.01 mol); or cyclohexylidenemalononitrile (9) (0.01 mol) in
30 mL of absolute ethanol. The reaction mixture was stirred at
25ꢀC for 2 h then left at RT overnight. The precipitated solid so
formed was filtered off, washed with water, and crystallized
from dimethylformamide to afford 7 and 11, respectively.
Alternative synthesis of 12.
Anhydrous sodium acetate
(0.01 mol) was added to a mixture of cyclohexylidenemalononitrile
(9) (0.01 mol) and malononitrile (4) (0.01 mol) dissolved in 30 mL of
absolute ethanol followed by two drops of water. The reaction mixture
was stirred at 25ꢀC for 2 h then left to stand at RT overnight. The
solid product so formed was filtered off, washed with cold water, and
recrystallized from dimethylformamide to afford compound 12.
The reaction of cyclohexanone (8) and malononitrile (4) in
absence of oxygen.
To a mixture of cyclohexanone (8)
(0.01 mol) and malononitrile (4) (0.02 mol) in ethanol (30 mL)
was added sodium acetate (0.01 mol), and argon gas was
streamed in the flask that was then closed and left at RT
overnight. To this reaction, mixture was added cold water
(10 mL) and neutralized with few drops of concentrated HCl,
and after extraction with ether, we have obtained the
condensation product 9 (yield 30%); identical to that obtained
according to the reported literature method [21].
[26] Weixing, S.; Miller, J. M. J Mass spectrometry 2003, 38(4), 438.
[27] Fei, H.; Qiu-Hong, P.; Ying, S.; Xue-Ting, Z.; Chang-Qing D.
J Mass Spectrometry 2008, 44(5), 633.
[28] Johannes, J. L. C.; Singleton, V. L. Am J Enol Vitic 1990, 41(1), 84.
[29] Talcott, S. T., Howard, L. R. J Agric Food Chem 1999, 47(5),
2109.
Acknowledgment. F. M. Abdelrazek thanks the Alexander von
Humboldt-Foundation (Germany) for the continuous support
through granting short research fellowships whenever applied for.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet