Reaction of methyl 1-bromocyclohexanecarboxylate with zinc and 3-Aryl-2-cyanopropenoic acids amides

Article abstract of DOI:10.1134/S1070363212070079

Methyl 1-bromocyclohexanecarboxylate reacts with zinc and amides or methylamides of 3-aryl-2-cyanopropenoic acids to give 5-aryl-1,3-dioxo-2- azaspiro[5.5]undecane-4-carbonitriles or 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5. 5]undecane-4-carbonitriles. Plei

Full text of DOI:10.1134/S1070363212070079

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 7, pp. 1228–1232. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.F. Kirillov, E.A. Nikiforova, S.N. Shurov, P.A. Slepukhin, M.I. Vakhrin, 2012, published in Zhurnal Obshchei Khimii, 2012,
Vol. 82, No. 7, pp. 1124–1128.
Reaction of Methyl 1-Bromocyclohexanecarboxylate
with Zinc and 3-Aryl-2-cyanopropenoic Acids Amides
N. F. Kirillova, E. A. Nikiforovaa, S. N. Shurova, P. A. Slepukhinb, and M. I. Vakhrina
a Perm State National Research University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: kirillov@psu.ru
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
Received June 9, 2011
Abstract—Methyl 1-bromocyclohexanecarboxylate reacts with zinc and amides or methylamides of 3-aryl-2-
cyanopropenoic acids to give 5-aryl-1,3-dioxo-2-azaspiro[5.5]undecane-4-carbonitriles or 5-aryl-2-methyl-1,3-
dioxo-2-azaspiro[5.5]undecane-4-carbonitriles.
DOI: 10.1134/S1070363212070079
The Reformatsky reagents have been found to
attach to the double bond of 3-aryl-2-cyanopropenoic
acids amides followed by the intermediates cyclization
to form the substituted piperidine-2,6-diones [1–3]. In
order to obtain the similar compounds involving the
spiro-carbon atom we studied the reaction of the
Reformatsky reagent derived from methyl 1-bromo-
cyclohexanecarboxylate and zinc with amides and
methylamides of 3-aryl-2-cyanopropenoic acid.
reagent to yield the intermediates IIa–IIe. The latter
are cyclized into the intermediate compounds IIIa–
IIIe by the nucleophilic attack of the amide nitrogen
atom on the carbonyl carbon atom of the ester group.
After the reaction mixture decomposing, we isolated
the substituted spiropiperidin-2,6-diones, namely 5-
aryl-2-methyl-1,3-dioxo-2-azaspiro[5.5]undecane-4-
carbonitriles IVa–IVe.
The composition and structure of compounds IVa–
IVe were confirmed by the elemental analysis, IR and
1H NMR spectroscopy. In the IR spectra of compounds
IVa–IVe there are the absorption bands in the ranges
According to our research, at the heating in a
benzene–ethyl acetate–HMPA mixture, the double
bond of methylamides Ia–Ie attaches the Reformatsky
CONHMe
O
C
2Zn, ArCH
Ia−Ie
OMe
CN
Br
ZnBr
2
Ar
BrZn
N
COOMe
COOMe
Me
O
CN
IIa−IIe
H Ar
N
H Ar
NC
NC
HOH (H+)
−Zn(OH)Br
BrZn
O
H
O
−MeOZnBr
O
N
O
Me
IIIa−IIIe
Me
IVa−IVe
I–IV, Ar = Ph (а), 4-BrC6H4 (b), 4-ClC6H4 (c), 4-MeOC6H4 (d), 3,4-(MeO)2C6H3 (e).
1228

REACTION OF METHYL 1-BROMOCYCLOHEXANECARBOXYLATE
1229
of 1660–1680 and 1710–1725 cm–1, belonging to the
carbonyl groups of the imide fragment. Occurrence of
only one set of signals in the 1H NMR spectra (CDCl3)
indicates that the compounds IVa–IVe are isolated as
one diastereomer. The most characteristic signals in
In order to explain these results, we calculated ab
initio the geometric characteristics and the total
energies (Etot, a.u.) of various forms of compound IVa
using the SCF MO LCAO method in the 6-31G(d)
basis. As can be seen from a comparison of the
calculated total energies, there is the most stable A
form of the compound, in which the chiral centers, the
C4 and C5 atoms, are S/R- and R/S-configured, respec-
tively. The piperidine ring is a flattened chair, and the
C5–H bond has an equatorial orientation. The cal-
culated dihedral angle НС4С5Н equals to 52.6°. The
JНС4С5Н coupling constant value was evaluated by us
according to the Karplus equation involving the
Bothner–By parameters [4]. The estimated value was
5.1 Hz, which is quite satisfactory agree with the
experiment.
1
the H NMR spectra are the doublets of the protons at
the C4,5 atoms in the regions of the 3.54–3.64 and
4.16–4.52 ppm (J 5.7 Hz). It is noteworthy that the
proton signals of the C2,6 atoms of aromatic ring are
broadened, probably due to the hindered internal
1
rotation around the C–Ar bond. In the H NMR
spectrum of compound IVc recorded at 50°C this
broad signal is converted into a doublet. However, at
this temperature a second set of signals manifests the
presence of a second isomer appearing probably owing
to the piperidine ring inversion.
In the 1H NMR spectra of the synthesized
compounds dissolved in DMSO-d6 there are two sets
of signals, explainable by the appearance of the second
isomer characterized by the coupling of the protons at
the C4 and C5 atoms (doublets) with the constant equal
to 12.9 Hz.
We assumed that in DMSO-d6 the most stable form
of A converts via the enol form B into the C form with
the S/S- or R/R-configured chiral centers. Due to the
inversion of piperidine ring the form C transforms into
the form D with transoid orientation of the Н–С4 and
Н–С5 bonds.
Ph
H
Ph H
Ph
H
Ph H
H
NC
H
NC
H
NC
HO
NC
5
4
3
1
2
O
N
O
N
O
O
N
O
O
N
O
Me
Me
Me
Me
А
B
C
D
Etot –951.9343 au
Etot –951.9119 au
Etot –951.9340 au
Etot –951.9271 au
In the form C the calculated dihedral angle НС4С5Н
is 89.3° that corresponds to the coupling constants
equal to 2.00 Hz, which contradict the experimental
data. In the form D the Н–С5 bond is axial; the
calculated dihedral НС4С5Н angle is 174.4°. The
similarly calculated coupling constant was equal to
12.9 Hz, which coincides with the experimental value.
Despite the fact that the calculated energy of the form
C is lower than that of the form D, the first form was
not found in a DMSO-d6 solution. Perhaps the form D
crystallize in the centrosymmetric space group of the
monoclinic system. General view and adopted in the
structural experiment numbering of the atoms of one
crystallographically independent molecule are shown
in the figure. The numbers of atoms of the second molecule
carry an additional index “A.” The geometrical param-
eters of the molecules (bond length and bond angles)
are close to each other and close to the standard values.
The torsion angle НС4С5Н (the H2AC2C3H3A and
H2AАC2АC3АH3AА groups in the struc-tural experiment)
equals to –51.2 and –52.0° for the first and the second
molecule, respectively, which agrees well with the
calculated data for a major diastereomeric form A.
is more efficiently solvated compared with the form C,
→
and the equilibrium C
D is shifted to the right.
←
However, the form A is more stable than D. Therefore
it is dominant in a DMSO-d6 solution.
Similarly, the reaction of the Reformatsky reagent
derived from methyl 1-bromocyclohexanecarboxylate
and zinc with amides of 3-aryl-2-cyanopropenoic acids
Va–Ve results in 5-aryl-1,3-oxo-2-azaspiro[5.5]
undecane-4-carbonitriles VIIIa–VIIIe via the inter-
mediates VIa–VIe and VIIa–VIIe.
Since the quantum-chemical calculations describe
the behavior of the isolated molecules in a gas phase,
we undertook a study of a single crystal of compound
IVa by the X-ray analysis. According to the X-ray
data, two crystallographically independent molecules
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1230
KIRILLOV et al.
CONH2
O
C
3Zn, ArCH
OMe
ZnBr
CN
Br
Va−Ve
3
Ar
BrZn
N
COOMe
2
COOMe
ZnBr
O
CN
VIa−VIe
H Ar
N
H Ar
NC
NC
HOH (H+)
−Zn(OH)Br
BrZn
H
O
−MeOZnBr
O
O
N
H
O
ZnBr
VIIa−VIIe
VIIIa−VIIIe
V–VIII: Ar = Ph (а), 4-BrC6H4 (b), 4-ClC6H4 (c), 3,4-(MeO)2C6H3 (d), 2.4-Cl2C6H3 (e).
1
Existence of only one set of the signals in the H
compounds in CDCl3 and DMSO-d6 were recorded on
a Mercury Plus-300 spectrometer (300 MHz) relative
to internal TMS.
NMR spectra of compounds VIIIa, VIIIc and VIIId
(solvent CDCl3) shows that these compounds are
isolated as single diastereomer. Since the compounds
VIIIb and VIIIe are practically insoluble in CDCl3
their H NMR spectra were obtained for the solutions
in DMSO-d6 and therefore contain the signals of two
The quantum-chemical calculations of various
forms of compound IVa was performed using a Firefly
(PC GAMESS, version 7.1.G) software package [5].
1
The X-ray analysis of compound IVa was carried
out on a Xcalibur-3 automatic four-circle diffracto-
meter equipped with CCD-detector at 295(2) K,
λ 0/71073 Å (MoKα). Data collection and processing
were carried out by the standard procedures [6], no
correction for absorption was introduced. The crystals
isomers.
EXPERIMENTAL
The IR spectra of compounds IV and VIII were
obtained on a Specord-75IR spectrophotometer for the
samples in vaseline oil. The NMR spectra of these
General view of the molecule of IVa by the X-ray data with 50% probability thermal ellipsoids.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 7 2012

REACTION OF METHYL 1-BROMOCYCLOHEXANECARBOXYLATE
1231
are monoclinic, space group P21/c; a 12.2673(3),
b 8.6846(2), c 29.7776(6) Å; β 95.293(2)°, μ 0.082 mm–1.
In the range of 52.72 < θ <28.29° were collected
15 858 reflections, of which 7580 are independent (Rint
0.0233), 5124 with I > 2σ(I). Completeness to θ <
28.29° is 96.7%. The structure solution and refinement
were performed using a SHELX software package [7].
The refinement was carried out by a full-matrix
anisotropic approximation F2 for all non-hydrogen
atoms. The hydrogen atoms were placed into the
geometrically calculated positions and included into
the refinement by an isotropic approximation with the
dependent thermal parameters by the rider model. The
final refinement results are: R1 0.0480, wR2 0.1260 [for
the reflections with I > 2σ(I)], R1 0.0685, wR2 0.1336
(for all reflections) at S 1.001. The peaks of maximal
and minimal residual electron density are 0.335 and
–0.268 eÅ–3, respectively. The results of the X-ray
diffraction experiments were reported in the
Cambridge structural data base (CCDC 863296).
[10Н, (СН2)5], 3.29 s (3Н, MeN), 3.58 d (1Н, CHAr, J
5.7 Hz), 4.42 d (1Н, СНCN, J 5.7 Hz), 6.89 br.s, 7.48
d (4Н, 4-BrC6H4, J 8.7 Hz). Found, %: С 57.78; Н
4.99, Br 21.52; N 7.33. С18Н19BrN2О2. Calculated, %:
С 57.61; Н 5.10; Br 21.29; N 7.47.
2-Methyl-1,3-dioxo-5-(4-chlorophenyl)-2-azaspiro-
[5.5]undecane-4-carbonitrile (IVc). Yield 2.35 g
(71%), mp 216–218°С. IR spectrum, ν, cm–1: 1665,
1
1720 (С=О). Н NMR spectrum, δ, ppm: 1.19–1.93 m
[10Н, (СН2)5], 3.32 s (3Н, MeN), 3.64 d (1Н, CHAr, J
5.7 Hz ), 4.52 d (1Н, СНCN, J 5.7 Hz), 7.03 br.s, 7.52
d (4Н, 4-ClC6H4, J 8.7 Hz). 1Н NMR spectrum (50°С),
δ, ppm: isomer 1, 1.19–1.93 m [(СН2)5], 3.29 s (MeN),
3.56 d (CHAr, J 5.7 Hz), 4.40 d (СНCN, J 5.7 Hz),
6.94 d, 7.32 d (4-ClC6H4, J 8.4 Hz); isomer 2, 1.19–
1.93 m [(СН2)5], 3.27 s (MeN), 3.51 d (CHAr, J 7.5 Hz),
4.12 d (СНCN, J 7.5 Hz), 7.02 d, 7.35 d (4-ClC6H4, J
8.7 Hz). Found, %: С 65.22; Н 5.89; Cl 10.50; N 8.61.
С18Н19ClN2О2. Calculated, %: С 65.35; Н 5.79; Cl
10.72; N 8.47.
5-Aryl-2-methyl-1,3-dioxo-2-azaspiro[5.5]unde-
cane-4-carbonitriles (IVa–IVe). A mixture of 3 g of
zinc as fine shavings, a catalytic amount of mercuric
chloride, 20 ml of anhydrous ethyl acetate, 20 ml of
anhydrous benzene, 1 ml of HMPA, 10 mmol of methyl-
amides of 3-aryl-2-cyanopropene acid and 25 mmol of
methyl 1-bromocyclohexanecarboxylate was refluxed
for 4 h, cooled, decanted from the zinc excess and
hydrolyzed with 5% acetic acid. The organic layer was
separated, and the aqueous layer was washed twice
with ethyl acetate. The extract was dried over
anhydrous sodium sulfate and concentrated. The target
compounds IVa–IVe were recrystallized from ethyl
acetate.
2-Methyl-5-(4-methoxyphenyl)-1,3-dioxo-2-aza-
spiro[5.5]undecane-4-carbonitrile (IVd). Yield 1.53 g
(47%), mp 169–170°С. IR spectrum, ν, cm–1: 1680,
1
1710 (С=О). Н NMR spectrum, δ, ppm: 1.23–1.97 m
[10Н, (СН2)5], 3.29 s (3Н, МеN), 3.56 d (1Н, CHAr, J
5.7 Hz), 3.78 s (3Н, ОМе), 4.16 d (1Н, СНCN, J
5.7 Hz), 6.84 d, 6.90 br. d (4Н, 4-MeOC6H4, J 8.7 Hz).
1Н NMR spectrum (DMSO-d6), δ, ppm (А:D = 3:1):
А, 1.23–1.97 m [(СН2)5], 3.16 s (МеN), 3.72 d (CHAr,
J 5.7 Hz), 3.75 s (ОМе), 5.23 d (СНCN, J 5.7 Hz),
6.87 d, 7.22 br.s (4-MeOC6H4, J 9.0 Hz); D, 1.23–1.97
m [(СН2)5], 3.09 s (МеN), 3.68 d (CHAr, J 12.9 Hz),
3.79 s (ОМе), 5.29 d (СНCN, J 12.9 Hz), 6.97 d, 7.22
br.s (4-MeOC6H4, J 8.4 Hz). Found, %: С 70.14; Н
6.61; N 8.42. С19Н22N2О3. Calculated, %: С 69.92; Н
6.79; N 8.58.
2-Methyl-1,3-dioxo-5-phenyl-2-azaspiro[5.5]un-
decane-4-carbonitrile (IVa). Yield 2.02 g (68%), mp
146–147°С. IR spectrum, ν, cm–1: 1680, 1725 (С=О).
1Н NMR spectrum, δ, ppm: 1.24–1.95 m [10Н, (СН2)5],
3.30 s (3Н, MeN), 3.60 d (1Н, CHAr, J 5.7 Hz), 4.45 d
(1Н, СНCN, J 5.7 Hz), 7.00 br.s, 7.31–7.36 m (5Н,
5-(3,4-Dimethoxyphenyl)-2-methhyl-1,3-dioxo-2-
azaspiro[5.5]undecane-4-carbonitrile (IVe). Yield
1.82 g (51%), mp 136–137°С. IR spectrum, ν, cm–1:
1
13
1660, 1715 (С=О). Н NMR spectrum, δ, ppm: 1.28–
Ph). C NMR spectrum, δ, ppm: 20.53, 21.18, 24.95,
31.11, 34.45 [(CH2)5], 27.75 (CH3N), 39.51 (C5), 45.35
(C6), 46.02 (C4), 114.57 (CN), 128.57, 128.71, 129.41,
134.91 (Ph), 163.91 (C3=O), 175.88 (C1=O). Found,
%: С 73.09; Н 6.91, N 9.27. С18Н20N2О2. Calculated,
%: С 72.95; Н 6.80; N 9.45.
1.97 m [10Н, (СН2)5], 3.29 s (3Н, МеN), 3.54 d (1Н,
CHAr, J 5.7 Hz), 3.81 s (3Н, ОМе), 3.85 s (3Н, ОМе),
4.44 d (1Н, СНCN, J 5.7 Hz), 6.52 br.s, 6.80 d (3Н,
3,4-(MeO)2C6H3, J 8.7 Hz). Found, %: С 67.21; Н
6.92; N 8.04. С20Н24N2О4. Calculated, %: С 67.40; Н
6.79; N 7.86.
5-(4-Bromophenyl)-2-methyl-1,3-dioxo-2-azaspiro-
[5.5]undecane-4-carbonitrile (IVb). Yield 2.44 g
(65%), mp 214–215°С. IR spectrum, ν, cm–1: 1675,
5-Aryl-1,3-dioxo-2-azaspiro[5.5]undecane-4-
carbonitriles (VIIIa–VIIIe) were prepared similarly
from 10 mmol of amides of 3-aryl-2-cycnopropenoic
1
1715 (С=О). Н NMR spectrum, δ, ppm: 1.21–1.88 m
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 7 2012

1232
KIRILLOV et al.
acids and 35 mmol of methyl 1-bromocyclohexane-
carboxylate.
5.7 Hz), 3.84 s (3Н, ОМе), 3.86 s (3Н, ОМе), 4.39 d
(1Н, СНCN, J 5.7 Hz), 6.63 s, 6.69 d, 6.82 d [3Н, 3,4-
(MeO)2C6H3], 8.19 s (1H, NH). Found, %: С 66.42; Н
6.36; N 8.36. С19Н22N2О4. Calculated, %: С 66.65; Н
6.48; N 8.18.
1,3-Dioxophenyl-5-phenyl-2-azaspiro[5.5]unde-
cane-4-carbonitrile (VIIIa). Yield 1.84 g (65%), mp
236–238°С. IR spectrum, ν, cm–1: 1705, 1725 (С=О),
1
3200 (NH). Н NMR spectrum, δ, ppm: 1.21–2.00 m
5-(2,4-Dichlorophenyl)-1,3-dioxo-2-azaspiro[5.5]-
undecane-4-carbonitrile (VIIIe). Yield 2.46 g (70%),
mp 293–295°С. IR spectrum, ν, cm–1: 1710, 1725
[10Н, (СН2)5], 3.62 d (1Н, CHPh, J 6.0 Hz), 4.40 d
(1Н, СНCN, J 6.0 Hz), 7.10–7.41 m (5Н, Ph), 8.14 s
(1H, NH). Found, %: С 72.68; Н 6.56; N 9.78.
С17Н18N2О2. Calculated, %: С 72.32; Н 6.43; N 9.92.
1
(С=О), 3160 (NH). Н NMR spectrum (DMSO-d6), δ,
ppm (А:D = 2:1): А, 1.10–2.12 m [10Н, (СН2)5], 4.44
d (1Н, CHAr, J 6.3 Hz), 4.80 d (1Н, СНCN, J 6.3 Hz),
7.09 d, 7.26 d, 7.57 s (3Н, Cl2C6H3, J 8.4 Hz ), 11.29 s
(1H, NH); D, 1.10–2.12 m [10Н, (СН2)5], 4.23 d (1Н,
CHAr, J 10.8 Hz), 4.70 d (1Н, СНCN, J 10.8 Hz), 7.34
d, 7.38 d, 7.51 s (3Н, Cl2C6H3, J 8.4 Hz), 11.17 s (1H,
NH). Found, %: С 58.39; Н 4.46; Cl 19.98; N 8.11.
С17Н16Cl2N2О2. Calculated, %: С 58.13; Н 4.59; Cl
20.19; N 7.98.
5-(4-Bromophenyl)-1,3-dioxo-2-azaspiro[5.5]un-
decane-4-carbonitrile (VIIIb). Yield 2.28 g (63%),
mp 249–250°С. IR spectrum, ν, cm–1: 1710, 1725
1
(С=О), 3205 (NH). Н NMR spectrum (DMSO-d6), δ,
ppm (А:D = 3:1): А, 1.10–1.97 m [10Н, (СН2)5], 3.59
d (1Н, CHAr, J 5.7 Hz), 4.63 d (1Н, СНCN, J 5.7 Hz),
7.08 d, 7.48 d (4Н, 4-BrC6H4, J 8.4 Hz), 11.01 s (1H,
NH); D, 1.10–1.97 m [10Н, (СН2)5], 3.49 d (1Н,
CHAr, J 10.5 Hz), 4.52 d (1Н, СНCN, J 10.5 Hz), 7.12
d, 7.52 d (4Н, 4-BrC6H4, J 8.4 Hz), 10.93 s (1H, NH).
Found, %: С 56.75; Н 4.88; Br 22.33; N 7.70.
С17Н17BrN2О2. Calculated, %: С 56.52; Н 4.74; Br
22.12; N 7.75.
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Ministry of Education and Sciences (project 1.12.11).
REFERENCES
1,3-Dioxo-5-(4-chlorophenyl)-2-azaspiro[5.5]un-
decane-4-carbonitrile (VIIIc). Yield 1.84 g (58%),
mp 243–245°С. IR spectrum, ν, cm–1: 1710, 1725
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1
(С=О), 3190 (NH). Н NMR spectrum, δ, ppm: 1.16–
2.02 m [10Н, (СН2)5], 3.59 d (1Н, CHAr, J 5.7 Hz),
4.37 d (1Н, СНCN, J 5.7 Hz), 7.09 d, 7.35 d (4Н, 4-
ClC6H4, J 8.4 Hz), 7.99 s (1H, NH). Found, %: С
64.72; Н 5.26; Cl 11.38; N 8.70. С17Н17ClN2О2.
Calculated, %: С 64.46; Н 5.41; Cl 11.19; N 8.84.
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p. 195.
5-(3,4-Dimethoxyphenyl)-1,3-dioxo-2-azaspiro-
[5.5]undecane-4-carbonitrile (VIIId). Yield 1.88 g
(55%), mp 184–185°С. IR spectrum, ν, cm–1: 1680,
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Oxford Diffraction Ltd., 2006.
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1.23–1.98 m [10Н, (СН2)5], 3.56 d (1Н, CHAr, J
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 7 2012