Reactions of methyl 1-bromocyclohexylcarboxylate with zinc and benzyl- or cyclohexylamides of 3-aryl-2-cyanopropenoic acids

Article abstract of DOI:10.1134/S1070363213060108

Methyl 1-bromocyclohexylcarboxylate reacts with zinc and benzyl- or cyclohexylamides of 3-aryl-2-cyanopropenoic acids to give methyl 1-(1-aryl-3-benzylamino)- or methyl 1-(1-aryl-3-cyclohexylamino)-3-oxo-2- cyanopropyl)cyclohexylcarboxylates whose structu

Full text of DOI:10.1134/S1070363213060108

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 6, pp. 1067–1070. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © N.F. Kirillov, E.A. Nikiforova, P.A. Slepukhin, M.I. Vakhrin, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 6,
pp. 936–939.
Reactions of Methyl 1-Bromocyclohexylcarboxylate
with Zinc and Benzyl- or Cyclohexylamides
of 3-Aryl-2-cyanopropenoic Acids
N. F. Kirillova, E. A. Nikiforovaa, 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 May 28, 2012
Abstract—Methyl 1-bromocyclohexylcarboxylate reacts with zinc and benzyl- or cyclohexylamides of 3-aryl-
2-cyanopropenoic acids to give methyl 1-(1-aryl-3-benzylamino)- or methyl 1-(1-aryl-3-cyclohexylamino)-3-
oxo-2-cyanopropyl)cyclohexylcarboxylates whose structure was determined by XRD analysis.
DOI: 10.1134/S1070363213060108
It was found previously that Reformatsky reagents
add to the double bond of amides of 3-aryl-2-
cyanopropenoic acids followed by cyclization of
intermediates to form substituted piperidine-2,6-diones
[1–4]. We have studied the reaction of the Refor-
matsky reagent I obtained from methyl 1-bromo-
cyclohexylcarboxylate and zinc, with benzyl- and
cyclohexylamides of 3-aryl-2-cyanopropenoic acids.
The Reformatsky reagent I in boiling benzene reacts
with unsaturated amide at the 1,4-positions to form
intermediates IIIa–IIId. After decomposing the
reaction mixture methyl 1-(1-aryl-3-benzylamino-3-
oxo-2-cyanopropyl)cyclohexylcarboxylates Va, Vb or
methyl 1-(1-aryl-3-oxo-2-cyano-3-cyclohexylpropyl)
cyclohexylcarboxylates Vc, Vd were isolated.
In this case there is no cyclization of adducts into
piperidine-2,6-diones through the attack of the
nitrogen atom on the ester carbonyl group. Probably, it
is caused by the bulky cyclohexyl substituent bonded
with an ester group and the substituents at the nitrogen
atom in the intermediates IIIa–IIId.
ZnBr
Br
2Zn
2
2
COOMe
COOMe
I
ArCH=C(CN)CONHR
−
COOMe
IIa−IId
ZnBr
H
COOMe
COOMe
COOMe
H
N
O
N
R
2HOH (H+)
R
R
N
OZnBr
OH
−2Zn(OH)Br
H
Ar
Ar
Ar
CN
IIIa−IIId
CN
Va−Vd
CN
H
H
H
IVa−IVd
II–V, R = C6H5CH2, Ar = 4-BrC6H4 (a), 3-BrC6H4 (b); R = C6H11, Ar = Ph (c), 3-BrC6H4 (d).
1067

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KIRILLOV et al.
Some bonds lengths, bond and torsion angles in compound
Va
mixture of one the two possible diastereomers. The
most characteristic signals are the doublets of doublets
of non-equivalent methylene protons of benzyl
substituent in the amide fragment of compounds Va,
Vb at 4.11–4.17 and 4.45–4.46 ppm and the protons
doublets of oxopropyl moiety in the ranges of 3.48–
3.55 and 3.92–4.04 ppm with spin-spin coupling
constants of 3.0–3.3 Hz. To establish the structure of
the compounds obtained we investigated compound
Va by XRD analysis.
Bond, angle
Br1–C14
Å, deg
1.919(5)
1.319(5)
1.458(5)
1.211(6)
1.310(6)
1.140(5)
1.223(4)
1.545(5)
113.2(4)
105.0(3)
110.2(3)
114.7(3)
179.4(4)
–96.8(4)
62.0(5)
Bond, angle
Br1А–C14А
Å, deg
1.903(4)
1.323(5)
1.467(5)
1.203(5)
1.324(6)
1.157(5)
1.216(4)
1.531(5)
111.9(4)
104.9(3)
110.0(3)
114.3(3)
178.6(4)
98.0(4)
N1–C5
N1А–C5А
N1–C25
N1А–C25А
O1–C1
O1A–C1A
C1–O2
C1A–O2A
N2–C17
N2А–C17А
According to the XRD analysis data, two
crystallographically independent molecules crystallize
in a chiral space group Р1 of triclinic system. Numbers
of the atoms of the second molecule were marked with
an additional index “A.” The molecules have similar
bond lengths and angles, but different absolute
configuration (see Table). In particular, the atoms C3
and C4 have S-configuration, and the atoms C4A and
C3A, R-configuration (Figs. 1 and 2). Despite the fact
that the composition of the unit cell is racemic, the
molecular organization is not centrosymmetrical. This
is due to the formation of intermolecular hydrogen
bonds N–H···O, by which the molecules are arranged
in a chain along b axis. In this case the non-
centrosymmetrical alternation of the molecules of
different configuration is preferable, where the bulky
groups at the atoms C2 and C2A and also the polar CN
groups are spatially separated and aryl substituents are
stacked as compact as possible (Fig. 3).
O3–C5
O3A–C5A
C4–C5
C4A–O5A
N1–C25–C18
C17–C4–C5
C17–C4–C3
C5–C4–C3
N2–C17–C4
C17C4C5N1
C1C2C3C11
C10C2C3C11
C6C2C3C11
C1C2C3C4
C2C3C4C17
N1А–C25А–C18A
C17A–C4A–C5A
C17A–C4A–C3A
C5A–C4A–C3A
N2А–C17А–C4A
C17AC4AC5AN1А
C1AC2AC3AC11А
C10AC2AC3AC11А
C6AC2AC3AC11А
C1AC2AC3AC4А
–59.2(4)
59.9(4)
–173.5(4)
–55.1(5)
–65.5(5)
168.9(3)
179.6(4)
68.6(4)
C2AC3AC4AC17А –167.7(3)
The composition and structure of compounds Va–
Vd were confirmed by the elemental analysis data and
IR and H NMR spectroscopy. The IR spectra of
Thus, the crystallization of compound Va is a rare
case of the formation of chiral triclinic crystal system
formed by two enantiomers.
1
compounds Va–Vd contain an absorption band in the
regions of 1660–1665 and 1730–1740 cm–1,
respectively, belonging to the carbonyls of ester and
amide groups. The H NMR spectra (CDCl3) indicate
that compounds Va–Vd were isolated as a racemic
EXPERIMENTAL
The IR spectra were obtained on a spectro-
photometer Specord-75IR from the samples in mineral
oil. The 1H NMR spectra were recorded in CDCl3 on a
1
Fig. 1. Ball-and-stick model of compound Va (first molecule) according to XRD data.
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REACTIONS OF METHYL 1-BROMOCYCLOHEXYLCARBOXYLATE
1069
Fig. 2. Ball-and-stick model of compound Va (second molecule) according to XRD data.
Fig. 3. Fragment of molecular packing of compound Va.
Mercury Plus-300 spectrometer (300 MHz) with
respect to internal TMS.
to F2 in anisotropic approximation for all non-
hydrogen atoms. The hydrogen atoms were placed into
the geometrically calculated positions and refined
isotropically with dependent thermal parameters by a
rider model. The final refinement results: R1 0.0418,
wR2 0.0840 [for reflections with I > 2σ(I)], R1 0.1035,
wR2 0.0893 (for all reflections) at Q-factor GOOF of
1.004. The absolute structure parameter is –0.002(7).
The peaks of maximal and minimal residual electron
density are 0.501 and –0.505 e Å–3. The results of
XRD diffraction experiments are deposited in the
Cambridge Structural Database (CCDC 900795).
The XRD diffraction analysis of compound Va was
performed on an automatic four-circle diffractometer
Xcalibur 3 equipped with CCD-detectors at 295(2) K
[λ(MoKα) 0.71073 Å). Collection and processing of
data obtained was carried out by the standard
procedure [5], the extinction correction was introduced
by multiscanning method [6]. The crystals are triclinic,
space group P1, a 9.3552(10), b 10.6498(10), c
12.8109(11) Å; α 86.843(7), β 75.502(8), γ 79.417(8)°,
μ 1.719 mm–1 . In the range of 2.87 <θ <28.28° 11339
reflections were collected, 6760 were independent (Rint
0.0207), including 3047 with I > 2σ(I). The
completeness for θ < 26.00° is 97.1%. The solution
and refinement of the structure was carried out using
the software package SHELX [7]. The structure was
refined by full-matrix least-square method with respect
General procedure for the preparation of
compounds Va–Vd. A mixture of 3 g of fine zinc
turnings, a catalytic amount of mercuric chloride,
20 ml of anhydrous ethyl acetate, 20 ml of anhydrous
benzene, 1 ml of HMPA, 10 mmol benzylamide (or
cyclohexylamide) of 3-aryl-2-cyanopropenoic acid and
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KIRILLOV et al.
25 mmol of methyl 1-bromocyclohexylcarboxylate
was refluxed for 4 h, cooled, decanted from an excess
of zinc and treated with 5% of acetic acid. The organic
layer was separated, and the aqueous layer was
extracted twice with ethyl acetate. After drying the
extract over anhydrous sodium sulfate, the solvent was
distilled off, and the target compound was recrys-
tallized from ethyl acetate.
(1Н, C3H, J 3.3 Hz), 3.53–3.63 m (1H, CHN), 3.77 s
(3Н, MeO), 3.92 d (1Н, C2H, J 3.3 Hz), 5.61 d (1H,
NH, J 8.4 Hz), 7.28 s (5Н, Ph). Found, %: С 72.84; Н
8.06; N 6.98. С24Н32N2О3. Calculated, %: С 72.70; Н
8.13; N 7.06.
Methyl 1-[1-(3-bromophenyl)-3-oxopropyl-2-cyano-
3-(cyclohexylamino)]cyclohexylcarboxylate
(Vd).
Yield 1.35 g (57%), mp 172–173°С. IR spectrum, ν,
cm–1: 3260 (NH), 1730 (С=О, ester), 1660 (С=О,
amide). 1Н NMR spectrum, δ, ppm: 0.70–2.38 m [20Н,
2(СН2)5], 3.48 d (1Н, C3H, J 3.3 Hz), 3.54–3.66 m
(1H, CHN), 3.79 s (3Н, MeO), 3.93 d (1Н, C2H, J 3.3 Hz),
5.73 d (1H, NH, J 6.9 Hz), 7.19 t (1H, J 7.8 Hz), 7.29
d (1H, J 7.8 Hz), 7.37 s, 7.43 d (4Н, 3-BrC6H4, J
7.8 Hz). Found, %: С 60.49; Н 6.70; Br 16.58; N 5.93.
С24Н31BrN2О3. Calculated, %: С 60.63; Н 6.57; Br
16.81; N 5.89.
Methyl 1-[3-(benzylamino)-1-(4-bromophenyl)-
3-oxopropyl-2-cyano]cyclohexylcarboxylate (Va).
Yield 1.04 g (43%), mp. 176–177°С. IR spectrum, ν,
cm–1: 3270 (NH), 1730 (С=О, ester), 1660 (С=О,
amide). 1Н NMR spectrum, δ, ppm: 1.04–2.37 m [10Н,
(СН2)5], 3.54 d (1Н, C3H, J 3.0 Hz), 3.78 s (3Н, MeO),
4.01 d (1Н, C2H, J 3.0 Hz), 4.11 d. d (1H, CHPh,
J 16.6, 4.8 Hz), 4.46 d. d (1Н, СНPh, J 16.6, 6.9 Hz),
6.33 br. s (1H, NH), 6.83 d (2H, J 7.5 Hz), 7.22–7.27
m (5Н, Ph), 7.14 d (2H, J 8.7 Hz), 7.40 d (4H, 4-
BrC6H4, J 8.7 Hz). Found, %: С 61.99; Н 5.74; Br
16.68; N 5.88. С25Н27BrN2О3. Calculated, %: С 62.12;
Н 5.63; Br 16.53; N 5.80.
ACKNOWLEDGMENTS
This work was supported by the Russian Ministry
of Education (project no. 3.3925.2011).
Methyl 1-[3-(benzylamino)-1-(3-bromophenyl)-
3-oxopropyl-2-cyano]cyclohexylcarboxylate (Vb).
Yield 0.92 g (38%), mp 158–159°С. IR spectrum, ν,
cm–1: 3270 (NH), 1730 (С=О, ester), 1660 (С=О,
amide). 1Н NMR spectrum, δ, ppm: 1.08–2.38 m [10Н,
(СН2)5], 3.55 d (1Н, C3H, J 3.3 Hz), 3.79 s (3Н, MeO),
4.04 d (1Н, C2H, J 3.3 Hz), 4.17 d. d (1H, CHPh, J
15.0, 4.8 Hz), 4.45 d. d (1Н, CHPh, J 15.0, 6.9 Hz),
6.34 br. s (1H, NH), 6.89 d (2H, J 7.2 Hz), 7.22–7.25
m (5Н, Ph), 7.16 t (1H, J 8.1 Hz), 7.27 d (1H, J 8.1
Hz), 7.41 s, 7.45 d (4H, 3-BrC6H4, J 8.1 Hz). Found,
%: С 62.23; Н 5.66; Br 16.41; N 5.94. С25Н27BrN2О3.
Calculated, %: С 62.12; Н 5.63; Br 16.53; N 5.80.
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