Synthesis and structure analysis of 4-benzyl-1-[(2E)-3-(3-bromo-4-hydroxy- 5-methoxyphenyl)prop-2-enoyl]piperazine hydrochloride

Article abstract of DOI:10.3184/174751913X13700888313361

4-Benzyl-1-[(2E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)prop-2-enoyl] piperazine hydrochloride was prepared from 3-(3-bromo-4-acetyloxy-5- methoxyphenyl)-2-propenoic acid and benzylpiperazine. Its piperazine ring exhibits a chair conformation.

Full text of DOI:10.3184/174751913X13700888313361

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 391
JULY, 391–393
Synthesis and structure analysis of 4-benzyl-1-[(2E)-3-(3-bromo-4-
hydroxy-5-methoxyphenyl)prop-2-enoyl]piperazine hydrochloride
Aibin Lina,b, Bing Tua, Zhongqi Caia and Ying Panb*
aZhejiang Pharmaceutical College, Ningbo, 315100, P. R. China
bDepartment of Chemistry, Shantou University Medical College, Shantou, 515041, P. R. China
4-Benzyl-1-[(2E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)prop-2-enoyl]piperazine hydrochloride was prepared from
3-(3-bromo-4-acetyloxy-5-methoxyphenyl)-2-propenoic acid and benzylpiperazine. Its piperazine ring exhibits a chair
conformation.
Keywords: ferulic acid, amide, piperazine, X-ray diffraction
Ferulic acid derivatives exhibit various pharmacological prop-
erties including antioxidant, anti-inflammation, and anticancer
activities.1–5 Amidation is often used in transformations for the
synthesis of pharmaceuticals, fine chemicals, and polymers.6–9
It is estimated that more than 25% of known drugs contain an
amide group.10 The most frequently used amide formations
involve the reaction of an amine (including ammonia) with
activated carboxylic acid derivatives11 or coupling with
carboxylic acids mediated by a coupling reagent.12
and the C6/C7/C8/C9/C10/C11 plane is 91.0°, between plane
1 and the C15/C16/C17/C18/C19/C20 plane is 58.2°, and
between the two phenyl rings is 125.9°. Importantly, the
piperazine ring of compound 2 exhibits an obvious chair
conformation (Fig. 2).
As shown in the packing of compound 2 (Fig. 3), there
exists one intramolecular hydrogen bond [C3–H3B···Cl] and
two intermolecular hydrogen bonds [O2–H2···O1i and C5–
H5A···Clii] (Table 3). Intramolecular and intermolecular inter-
actions play a major role in stabilising the molecules in the
unit cell.
Previously, we have reported a series of amides which
contain a carbonyl from ferulic acid and a nitrogen from
piperazine.13,14 However, these studies failed to confirm the
conformation of piperazine ring. Here we report the synthesis
of4-benzyl-1-[(2E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-
prop-2-enoyl]piperazine hydrochloride (2). This novel com-
Experimental
Melting points were determined on an XT4-80X micro melting point
apparatus and uncorrected. IR spectra were taken on a Nicolet Magna
750 spectrophotometer (KBr pellets). 1H NMR spectra were recorded
1
pound was characterised by IR, H NMR, MS and elemental
analysis, and its structure was confirmed by single-crystal
X-ray diffraction.
Results and discussion
Compound 2 was synthesised as shown in Scheme 1. 3-(3-
Bromo-4-acetyloxy-5-methoxyphenyl)-2-propenoic acid reacted
with oxalyl chloride to generate an acid chloride intermediate.
The latter was amidated with benzylpiperazine. Then the
deprotection of the acetyl was prepared in situ with sodium
hydroxide. Finally the salification of benzylpiperazine yielded
the target compound. The coupling constant of C14=C13
Fig.1 Themolecularstructureof2,shownwith30%probability
displacement ellipsoids.
1
(J = 15.2 Hz) in H NMR matched the character for the E
configuration of double bonds.
The molecular structure of compound 2 is illustrated in
Fig. 1. Selected bond lengths and angles are listed in Table 1.
In the molecule (Fig. 1), the C14=C13 bond is a typical double
bond, and shows an E configuration clearly. The bond angles
of C14–C13–C12 and C13–C14–C15 are 122.6 (6)° and 124.5
(5)° respectively. The N1–C2, C1–C2, N2–C1, N2–C4, C3–
C4, and N1–C3 bonds correspond to typical single bonds.
In compound 2, atoms C1, C2, C3 and C4 are coplanar, with
the largest deviation from the plane (plane 1) being –0.0147 Å
for atom C3. The least-squares plane is listed in Table 2. The
adjacent N1 and N2 atoms deviate from plane 1 by 0.6499 and
–0.6622 Å respectively. The dihedral angle between plane 1
Table 1 Selected bond lengths (Å) and angles (°) of 2
Compound 2
Bond lengths
N1–C2
1.463 (7)
1.517 (9)
1.491 (7)
1.334 (8)
N2–C4
C3–C4
C3–N1
1.502 (7)
1.508 (8)
1.468 (7)
C1–C2
N2–C1
C14–C13
Bond angles
C14–C13–C12
C13–C14–C15
N1–C2–C1
122.6 (6)
124.5 (5)
111.5 (5)
N1–C3–C4
N2–C1–C2
N2–C4–C3
109.0 (5)
110.2 (5)
110.7(5)
Scheme 1 Synthesis of 2.
* Corresponding. E-mail: ypan@stu.edu.cn

392 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 Least-squares plane of C1, C2, C3 and C4
4-Benzyl-1-[(2E)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)prop-2-
enoyl]piperazine hydrochloride (2): The residue of 1 was diluted with
CHCl3 (10 mL) and added dropwise to a stirred solution of benzylpi-
perazine (1.242 g, 7.0 mmol) and Et3N (2.11 mL) in CHCl3 (10 mL).
The mixture was stirred at room temperature and monitored by TLC
(EtOAc/CHCI3=4:1, v/v). After completion of the reaction, the mix-
ture was washed three times with 5% NaHCO3 (10 mL). The organic
phase was washed with water (10 mL) and evaporated under reduced
pressure. The residue was diluted with EtOH (25 mL) and stirred
under reflux, while NaOH/EtOH (2 M, 25 mL) was poured into the
mixture. Then it was stirred under reflux for 15 min and evaporated
under reduced pressure. The residue was dissolved in water (60 mL).
Its pH was adjusted to 5–6 by adding 20% H2SO4 and adjusted to 7 by
adding 5% NaHCO3. Then the mixture was extracted twice with
EtOAc (20 mL). The organic phase was washed twice with 5%
NaHCO3 (20 mL), dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The residue was diluted with EtOH (8 mL) and
poured into a saturated solution of HCl in EtOH (15 mL). The mixture
was stored at 5 °C for 72 h. The resulting precipitate was filtered,
washed with EtOH and dried. Recrystallisation from 97% EtOH
gave colourless needles. Crystals suitable for X-ray diffraction were
obtained by slow evaporation in 97% EtOH at room temperature.
Orthonormal equation
of plane 1
5.283 x + 5.879 y + 7.191 z = 0.2399
Atom
C1
C2
C3
C4
–0.0145 0.0146 –0.0147 0.0145
Fig. 2 A chair conformation of compound 2, shown with 30%
probability displacement ellipsoids.
1
Yield, 17.6%. m.p. 195–197 °C. H NMR (400 MHz, DMSO-d6)
δ: 3.87 (s, 3H, ArOCH3), 4.34 (s, 2H, ArCH2), 3.00–4.55 (m, 8H,
piperazine), 7.15 (d, J = 15.2 Hz, 1H, COCH=), 7.33 (d, J = 1.6 Hz,
1H, ArH), 7.44 (d, J = 15.2 Hz, 1H, ArCH=), 7.55 (d, J = 1.6 Hz, 1H,
ArH), 7.46–7.61 (m, 5H, ArH), 9.93 (s, 1H, ArOH), 11.28 (s, 1H,
HCl). IR(KBr, cm−1) v: 3247, 3009, 1643, 1597, 1574, 1502, 1280.
MS (ESI) m/z: 431.3 [M+H]+, 433.1 [M+2+H]+. Anal. Calcd for
C21H24BrClN2O3 (466.07): C, 53.92; H, 5.17; N, 5.99. Found: C,
53.95; H, 5.10; N, 5.95%.
Crystal data of 2: A colourless needle of dimension 0.38 × 0.12 ×
0.10 mm3 was used for data collection with a Rigaku R-AXIS RAPID
diffractometer with graphite monochromated MoKα radiation (λ =
0.71073 Å). A summary of the crystal data is presented in Table 4.
The structure was solved by direct method procedures as imple-
mented in SHELXS9715 program. The positions of all the non-hydro-
gen atoms were included in the full-matrix least-squares refinement
using SHELXL9716 program. H atoms were added at calculated posi-
tions and refined using a riding model. H atoms were given isotropic
displacement parameters equal to 1.2 (or 1.5 for methyl H atoms)
times the equivalent isotropic displacement parameters of their parent
atoms. C–H distances were set to 0.93 Å for phenyl H atoms, 0.96 Å
for methyl H atoms, and 0.97 Å for methylene H atoms, while O–H
distances were set to 0.82 Å.
Fig. 3 A portion of the crystal packing of 2. Hydrogen bonds
are shown as dashed lines.
Table 3 Hydrogen-bond geometry bond lengths (Å) and
angles (°)
Table 4 Crystal data and structure refinement
Chemical formula
C21H24BrClN2O3
Donor–H···Acceptor
D—H
H···A
D···A
D—H···A
Colour/shape
Colourless/needle
466.76
O2–H2···O1i
C3–H3B···Cl
C5–H5A···Clii
0.82
0.97
0.97
2.05
2.78
2.65
2.757 (6)
3.541 (7)
3.600 (7)
145
136
167
Formula weight
Temperature/K
Wavelength/Å
Crystal system
Space group
293 (2)
0.71073
Monoclinic
P 21/c
Symmetry codes: (i) −x, y−1/2, −z+1/2; (ii) −x−2, −y+1, −z.
Unit cell dimensions
a = 6.4698 (13) Å
b = 14.136 (3) Å
c = 22.981 (5) Å
2090.3 (8)
on a BrukerAvance (400 MHz) spectrometer using deuterated dimeth-
ylsulfoxide (DMSO-d6) as the solvent. Chemical shifts were reported
in ppm relative to the solvent residual peak. The coupling constants
were reported in Hz. MS spectra were acquired on an ion trap mass
spectrometer (ABI QTRAP). Elemental analyses were operated on
an Elmentar Vario EL Ш apparatus, and the results were within the
accepted range of the calculated values. All purchased starting
materials and reagents were used without further purification. Oxalyl
chloride was purchased from Sigma-Aldrich.
3-(3-Bromo-4-acetyloxy-5-methoxyphenyl)-2-propenoic acyl chlo-
ride (1): Compound 1 (1.834 g, 5.8 mmol) was prepared according to
the procedure of Lin et al.14 and pyridine (0.6 mL) was mixed with
CHCl3 (10 mL) and stirred. Oxalyl chloride (0.7 mL, 7.6 mmol) was
added slowly to this suspension. After being stirred at room tempera-
ture for 1h, the mixture was evaporated under reduced pressure. The
residue (1.834 g, 5.8 mmol) was used for the next reaction without
further purification.
Volume/Å3
Z
4
Density (calculated)/g cm−3
Absorption coefficient/mm−1
θ range for data collection/deg
Limiting indices
1.483
2.118
3.02–27.44
–8/7, –18/18, –29/29
19763 / 4777 (Rint = 0.0819)
Multi–scan
Reflections collected/unique
Absorption correction
Max. and min. transmission
Data/restraints/parameters
Extinction coefficient
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
0.809, 0.745
4777 / 0 / 258
0.019 (3)
1.133
R1 = 0.0685, wR2 = 0.1683
R1 = 0.1455, wR2 = 0.2469
1.229, −1.885
Largest diff. peak and hole/e Å−3

JOURNAL OF CHEMICAL RESEARCH 2013 393
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We are grateful to the Guangdong Provincial Science and
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Received 11 February 2013; accepted 14 April 2013
Paper 1301790 doi: 10.3184/174751913X13700888313361
Published online: 18 July 2013
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