The reaction of cyclohexanone azine with cyanoacetic acid-acetic anhydride

Article abstract of DOI:10.1002/jhet.5570450545

(Chemical Equation Presented) The reaction of cyclohexanone azine with a reagent produced by brief heating of cyanoacetic acid with acetic anhydride produced a highly substituted dihydropyrazolone.

Full text of DOI:10.1002/jhet.5570450545

Sep-Oct 2008
1513
The Reaction of Cyclohexanone Azine with
Cyanoacetic Acid–Acetic Anhydride
Azadeh Nakhai†, Jim Raftery‡, Jan Bergman†*, and John A. Joule‡
† Department of Biosciences and Nutrition, Unit of Organic Chemistry,
SE-141 57, Huddinge, Sweden
E-mail: Jan.Bergman@biosci.ki.se
‡ The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received February 19, 2008
O
O
NC
Ac2O,
N
N
OH
N
CN
N
95 oC, 5 min
NC
O
The reaction of cyclohexanone azine with a reagent produced by brief heating of cyanoacetic acid with
acetic anhydride produced a highly substituted dihydropyrazolone.
J. Heterocyclic Chem., 45, 1513 (2008).
INTRODUCTION
N
The reagent which can quickly be prepared from
cyanoacetic acid and acetic anhydride (10 min, 95 °C) has
been demonstrated to be a powerful means for N- and
C-cyanoacetylation [1,2]. Thus, molecules like 1 (from
indole) and 2 (from 2-cyanoaniline) can readily be
prepared (Figure 1).
NH
N
N
3
4
Cl
CN
O
O
CN
5
NH
N
Figure 2
H
O
CN
2
1
conditions), where clearly two units of the reagent had
been incorporated. Bearing in mind the conversion of 3
into 4 on acid treatment, we initially considered structure
Figure 1
1
Currently there is a strong interest in the synthesis and
biological properties of pyrazoles [3-6], and in this
context we contemplated hydrazones and azines as readily
available precursors to such systems. As a first probe, the
azine 3 of cyclohexanone was selected because this
molecule is known to be convertible into the hexahydro-
indazole derivative 4 (a 4,5-dihydropyrazole) by reaction
with oxalic acid, as was first reported by Stollé and
Hanusch in 1930 [7]. The structure of 4 was later
confirmed by Kost and Grandberg [8] and it was also
independently prepared from 5 [9] (Figure 2).
6 for this product. However since the H NMR spectrum
revealed the presence of a typical alkenic CH-signal, this
assignment was reconsidered and structure
7 was
considered as a possible structure. Further NMR analysis
contradicted even this hypothesis and the molecule was
therefore subjected to an X-ray analysis which gave
conclusive evidence for the 4,5-dihydro-5H-pyrazol-3-one
structure 8 (Figure 3). Details of the structural analysis are
given in the Experimental Section and a Chem3D
representation of the molecule is shown in Figure 4. There
are several intriguing features of the structure which merit
comment.
RESULTS AND DISCUSSION
There are two amide units in the structure 8 but they are
quite different. The nitrogen of the five-membered ring
amide is, as one would anticipate, essentially planar, with
the sum of the angles around the nitrogen being 357.8°.
However, the adjacent cyanoacetamide nitrogen is far
Exposure of the azine 3 to the standard reagent
(cyanoacetic acid dissolved for 5 min in acetic anhydride
at 95 °C) at 40 °C gave, after work-up, a product,
C18H22N4O2, in 40-80% yield (depending on the

1514
A. Nakhai, J. Raftery, J. Bergman, and J. A. Joule
Vol 45
intramolecular cyclisation due to the acidity of the
cyanoacetamide hydrogen (arrows on 12) would lead to 8.
In this context, the reported formation of 4-cyano-3-
pyrazolidone from the corresponding hydrazone [10] and
also the purported formation of 3-aryl-4,5,6,7-tetra-
hydroindazoles upon treatment of N-cyclohexylidene-
cyanoacetyl hydrazide with benzaldehyde derivatives [11]
is of considerable interest.
CN
CN
N
N
N
O
N
O
O
O
NC
NC
7
6
Scheme 1
O
N
N
CN
N
N
NC
O
O
O
O
3
Ac2O
NC
NC
OH
O
O
95 oC, 5 min
8
9
Figure 3
O
O
O
NC
CN
CN
O
N
N
N
N
9
10
11
OAc
O
H
O
CN
H
N
N
N
N
CN
NC
NC
O
O
12
8
The 13C-NMR spectrum of 8 indicated that it is unstable
in solution, because the spectrum of 8 in DMSO solution
changed with time. Thus the 18 original signals were
slowly replaced by a new set of 18 signals. Thus, for
instance, the signal for the spirocyclic carbon atom in 8 at
73.1 ppm was slowly replaced by a new signal at 60.2
ppm.
Figure 4 Chem3D representation of compound 8 using the atomic
co-ordinates established by X-ray analysis.
The same changes were observed in an ethanol solution,
but over a longer period of time. However, with the
addition of water to the ethanol solution these changes
occurred faster. The conversion could be completed by
heating an aqueous alcoholic solution of 8 to 75 °C when
cooling resulted in precipitation of a product in 80%
yield. The changed product was shown to have the
elemental composition C15H21N3O and was assigned
structure 13 (Figure 5). Thus, the NMR spectrum of 13
showed that the cyanoacetyl unit was absent, but rather
surprisingly, the enehydrazide functionality was intact – it
had not been hydrolysed.
Heating compound 8 at reflux in aqueous ethanol for a
longer period did bring about further hydrolysis and the
resulting bicyclic hydrazide 14 could be isolated in 70%
yield. The structure was initially established by a
consideration of spectroscopic data – for example, the
from planar, with the sum of its angles being 344.7° –
substantially pyramidalised. There are two copies of the
molecule in the asymmetric unit, which from the choice
made are an enantiomorphic pair. The five-membered
dihydropyrazolone ring takes an envelope conformation,
with the spiro carbon being 0.634 and 0.621 Å out of the
average plane of the other four atoms in the two forms.
Scheme 1 shows a plausible mechanism for the
formation of pyrazolone derivative 8. Imine N-acylation
of azine 3 by the reagent 9 which is prepared from
cyanoacetic acid and acetic anhydride, produces the
iminium salt 10, which by deprotonation, would then give
an intermediate enamide of structure 11. A second N-
acylation of the remaining imine 11 followed by

Sep-Oct 2008
The Reaction of Cyclohexanone Azine with Cyanoacetic Acid–acetic Anhydride
1515
Büchi B-545 capillary melting point apparatus and are
uncorrected. Data for the two X-ray analyses have been
deposited at the Cambridge Crystallographic Data Centre under
the CCDC numbers 669439 (compound 8) and 669440
(compound 14) and can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
Cyclohexanone azine (3). This compound was prepared
according to ref. [13], as yellow crystals, mp 33-34 °C (lit [13]
35 °C); IR (neat) 2935, 2919, 2850, 1630, 1436, 1313, 1130,
988 cm-1.
spirocyclic carbon atom resonated at 63.3 ppm and the
corresponding carbon in 15 [12] resonated at 62.3 ppm
(Figure 5). The structure of 14 was confirmed by an X-ray
analysis, the details of which are given in the
Experimental Section and a Chem3D representation of the
molecule is shown in Figure 6. Here again, there is
interest in the three different nitrogen situations: in
addition to the nitrile nitrogen, there is a five-membered
amide nitrogen and a hydrazine nitrogen in a five-
membered ring. The amide nitrogen is perfectly planar,
with the sum of angles being 360.1°. The hydrazine
nitrogen has three angles (107.4°, 106.9° and 103.8°)
which are very close to those around ammonia (107°), the
smallest being the internal ring angle.
4-Cyano-1-cyanoacetyl-2-(cyclohexen-1-yl)-1,2-diazaspiro-
[4.5]decan-3-one (8). Cyanoacetic acid (6.2 g, 72.9 mmol) and
Ac2O (20 mL) were heated to 95 °C for 5 min. The solution was
cooled to 40 °C and cyclohexanone azine [13] (7 g, 36.5 mmol)
was added. The reaction mixture was heated to 70 °C for 15
min. After leaving at rt overnight the product had formed as a
precipitate which was collected, washed with a small volume of
acetic acid, and dried at room temperature in the air to yield 8
(5.2 g, 44%) as a white solid, mp 152-153 °C; IR (neat) 2933,
2864, 2257, 2250, 1714, 1664, 1324, 1207 cm-1; 1H NMR
(DMSO-d6) ꢀ 5.77-5.71 (m, 1H, CH), 4.89 (s, 1H, CH), 3.98 (d,
JAB=19.3 Hz, 1H, CHA), 3.80 (d, JAB=19.3 Hz, 1H, CHB), 2.44-
1.21 (m, 18H, 9 CH2); 13C NMR (DMSO-d6) ꢀ 168.1 (s), 164.2
(s), 133.9 (s), 119.4 (d), 115.4 (s), 114.1 (s), 73.1 (s), 46.8 (d),
31.5 (t), 31.4 (t), 28.2 (t), 24.3 (t), 24.2 (t), 23.6 (t), 22.5 (t), 21.8
(t), 21.7 (t), 21.0 (t). Calcd for C18H22N4O2: C, 66.24; H, 6.79; N,
17.16%. Found: C, 66.20; H, 6.79; N, 17.25%.
Crystal structure determination. Data were collected on a
Bruker Smart Apex CCD diffractometer. Wavelength: 0.71073
Å; Temperature: 100(2) K; Reflections collected/unique:
26285/6927 [R(int) = 0.0759]; Completeness to theta = 26.37:
99.7%; Space group: C2/c; a = 27.216(2) Å; b = 9.5770(9) Å ꢁ
= 103.073(2) deg.; c = 26.798(2) Å; V= 6803.8(11) ÅꢀꢁꢂZ=16; R
indices [I>2ꢃ(I)]: R1 = 0.0548, wR2 = 0.1020; R indices (all
data): R1 = 0.1020, wR2 = 0.1151.
O
O
N
HN
HN
CN
CN
HN
13
14
O
HN
HN
15
Figure 5
The structure was solved with SIR2004 [14] and refined with
SHELXL97 [15]. There were two molecules in the asymmetric
unit.
2-Cyclohex-1-enyl-3-oxo-1,2-diaza-spiro[4.5]decane-4-
carbonitrile (13). Compound 8 (2.0 g), ethanol (35 mL) and
H2O (5 mL) were heated to 75 °C for 5 min. After 6 h at rt the
product had formed as white crystals which were collected,
washed with chilled ethanol and dried at room temperature to
yield 13 (1.3 g, 80%), mp 113-115 °C; IR (neat) 3212, 2921,
1
2858, 2249, 2235, 1686, 1673, 1378 cm-1; H NMR (DMSO-d6)
ꢀ 5.97 (s, 1H, NH), 5.82-5.77 (m, 1H, CH), 4.15 (s, 1H, CH),
2.45-1.14 (m, 18H, 9 CH2); 13C NMR (DMSO-d6) ꢀ 163.9 (s),
134.6 (s), 115.6 (s), 114.8 (d), 60.2 (s), 47.5 (d), 33.2 (t), 30.2
(t), 25.3 (t), 24.8 (t), 23.5 (t), 22.0 (t), 21.4 (t), 21.3 (t), 21.3 (t).
Calcd for C15H21N3O: C, 69.47; H, 8.16; N, 16.20%. Found: C,
69.15; H, 8.16; N, 16.21%.
4-Cyano-1,2-diazaspiro[4.5]decan-3-one (14). Compound 8
(2.0 g), ethanol (35 mL) and H2O (5 mL) were heated to reflux for
2.5 h. After leaving at rt overnight the product had formed as a
precipitate which was collected, washed with ethanol, and dried at
room temperature in the air to yield 14 (1.4 g, 70%) as a yellow
solid, mp 92 °C; IR (neat) 3225, 3078, 2938, 2857, 2244, 1691,
1453, 910 cm-1; 1H NMR (DMSO-d6) ꢀ 9.62 (s, 1H, NH), 5.43 (s,
1H, NH), 3.88 (s, 1H, CH), 1.83-1.11 (m, 10H, 5 CH2); 13C NMR
(DMSO-d6) ꢀ 168.6 (s), 115.9 (s), 63.3 (s), 45.3 (d), 33.6 (t), 30.5
(t), 24.8 (t), 21.3 (t), 21.3 (t). Calcd for C9H13N3O: C, 60.32; H,
7.31; N, 23.45%. Found: C, 60.38; H, 7.31; N, 23.38%.
Figure 6 Chem3D representation of compound 14 using the atomic co-
ordinates established by X-ray analysis.
EXPERIMENTAL
NMR data were recorded on a Bruker DPX at 300.1 MHz for
1H and 75.5 MHz for 13C, respectively. IR spectra were acquired
on a Perkin-Elmer FT-IR 1600 spectrophotometer. Elemental
analyses were performed by LSM Lab, Uppsala, Sweden.
Melting points were determined on a Leica Kofler hot stage or a

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A. Nakhai, J. Raftery, J. Bergman, and J. A. Joule
Vol 45
[4] Chornous, V. O.; Bratenko, M. K.; Vovk, M. V. Zhur. Org.
Farm. Khim. 2003, 1, 35-50.
Crystal structure determination. Data were collected on a
Bruker Smart Apex CCD diffractometer. Wavelength: 0.71073
Å; Temperature: 100(2) K; Reflections collected/unique:
14039/2132 [R(int) = 0.0491]; Completeness to theta = 25.00:
100.0%; Space group: C2/c; a = 8.0700(6) Å; b = 9.9362(8) Å; c
= 22..0345(18) Å; V= 1766.8(2) Åꢀꢁꢂ Z= 8; R indices [I>2ꢃ(I):
R1 = 0.0457, wR2 = 0.1058; R indices (all data): R1 = 0.0555,
wR2 = 0.1108.
[5] Orth, R. E. J. Pharm. Sci. 1968, 57, 537-556.
[6] See yearly reviews as chapter 5.4 in Prog. Heterocycl. Chem.
·
[7] Stolle, R.; Hanusch, F. Chem. Ber. 1930, 63, 2211-2215.
[8] Kost, A. N.; Grandberg, I. I. Zh. Obshch. Khim. 1955, 25,
2064-2070.
[9] Terent'ev, A. P.; Kost, A. N.; Saltykova, Y. V.; Ershov, V. V.
Zh. Obshch. Khim. 1956, 26, 2925-2928.
The structure was solved with SIR2004 [14] and refined with
SHELXL97 [15].
[10] Ovcharenko, V. V.; Terent'ev, P. B.; Avetisyan, A. A.;
Kagramanyan, A. A. Khim. Geterotsikl. Soedin. 1995, 1525-1530.
[11] Hussein, A. H. M. Z Naturforsch., B. 1998, 53, 488-494.
[12] Johnson, P. Y.; Hatch, C. E., III. J. Org. Chem. 1975, 40,
3502-3510.
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