N-2-Hydroxybenzaldehyde acylhydrazone-Fe(iii) complex: Synthesis, crystal structure and its efficient and selective N-methylation

Article abstract of DOI:10.1039/c4dt00121d

N-Methyl-N′-2-hydroxybenzaldehyde acylhydrazones have been chemospecifically synthesized in good yield by N-methylation of the Fe(iii) complexes of N-2-hydroxybenzaldehyde acylhydrazones with methyl iodide in tetrahydrofuran. The reaction proceeds with the exclusive formation of the N-methyl derivative without any concurrent O-methylation side reactions. In addition, the N-methylation reaction occurred simultaneously with a complete deprotection step (elimination of the metal ion). As a result, the N-methyl product was obtained in excellent purity without time-consuming chromatographic workup. A free N-2-hydroxybenzaldehyde acylhydrazone ligand could not be methylated under the same conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4dt00121d

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N-2-Hydroxybenzaldehyde acylhydrazone–Fe(III)
complex: synthesis, crystal structure and its
efficient and selective N-methylation†
Cite this: Dalton Trans., 2014, 43,
7554
Zhiyou Li,a Lamei Wu,*a Tao Zhang,a Zhengxi Huang,a Guofu Qiu,b
Zhongqiang Zhoua and Longfei Jina
N-Methyl-N’-2-hydroxybenzaldehyde acylhydrazones have been chemospecifically synthesized in good
yield by N-methylation of the Fe(III) complexes of N-2-hydroxybenzaldehyde acylhydrazones with methyl
iodide in tetrahydrofuran. The reaction proceeds with the exclusive formation of the N-methyl derivative
without any concurrent O-methylation side reactions. In addition, the N-methylation reaction occurred
simultaneously with a complete deprotection step (elimination of the metal ion). As a result, the N-methyl
product was obtained in excellent purity without time-consuming chromatographic workup. A free N-2-
hydroxybenzaldehyde acylhydrazone ligand could not be methylated under the same conditions.
Received 16th January 2014,
Accepted 3rd March 2014
DOI: 10.1039/c4dt00121d
www.rsc.org/dalton
ate,1,15 LDA, NaHMDS, LiHMDS, or silver oxide (Ag2O).2 The
other approach is indirect methylation either by way of inter-
Introduction
N-Acylhydrazone and N-methyl-N′-acylhydrazone derivatives mediate 5-oxazolidinones,16 or application of the intramolecu-
have recently been applied in the synthesis of phosphodiester- lar or intermolecular azomethine imine cycloaddition to the
ase-4 (PDE4) inhibitors, cardiovascular drug candidates, nema- construction of N-alkyl-N′-acylhydrazone derivatives.17–21
ticidal agents and antimycobacterials. The N-methylation of N-Methyl-N′-acylhydrazones have been synthesized by direct
amide bonds can effectively improve the pharmacological pro- N-methylation of the corresponding N-acylhydrazones with
perties of synthetic drugs1–5 or peptides.6–9 N-methylation of methyl iodide in the presence of potassium carbonate.1
amides has always proven to be more difficult than for amines. However, this approach is unsuitable for N-methylation of N-2-
Unlike the pyramidal arrangement of bonds in ammonia and hydroxybenzaldehyde acylhydrazone. The intramolecular
amines, the bonds to the nitrogen in amides lie in the same hydrogen bonds of OH–N (imine) and NH–O (H)22 are likely to
plane. The electron-withdrawing inductive effect of the carbo- cause difficulties in the methylation of amide and hydroxyl
nyl group and the electron-releasing effect of the lone pair groups, respectively.
donation from the amide nitrogen decrease its nucleophilic
Complexation by metal ions can achieve selective synthesis
character. Therefore, many researchers have been seeking by promoting or suppressing side reactions at the sites of com-
simple and efficient methodologies for the N-methylation of plexation.23 When an organic molecule contains several reac-
amides. Currently, N-methylation of amides in the solid or tive sites, it often exhibits a considerably different reactivity
solution phase is often achieved by one of two common when complexed with a metal ion compared to its uncom-
approaches. One is direct methylation using a methylating plexed state. This rationale prompted us to examine the effects
agent, such as dimethyl sulfate, methyl iodide or diazo- of metal ions on the alkylation reaction of N-acylhydrazone.
methane,10 in the presence of various bases such as sodium N-Acylhydrazone ligands can coordinate to various metal ions
hydride,4,11–14 potassium tert-butoxide,2 potassium carbon- as tridentate ligands through the imine N, amide O and
phenolate O atoms.22,24 The two electron-withdrawing coordi-
nation bonds, imine-N-metal and amide-O-metal, stabilize the
negative charge of the amide N ion, permitting it to be easily
deprotonated and methylated with methylating agents in the
aKey Laboratory of Catalysis and Materials Science of the State Ethnic Affairs
Commission & Ministry of Education, South-Central University for Nationalities,
presence of a weak base. At the same time, formation of such
a phenolate-O-metal coordinate linkage could suppress the
O-methylation side reactions of the phenol. The formation of
ligand–metal ion coordinate bonds also interrupts the intra-
molecular hydrogen bonding of OH–N (imine) and NH–O (H)
to facilitate the N-methylation of amides (Scheme 1).
Wuhan, 430074, P. R. China. E-mail: wlm52875@163.com; Fax: +86-27-67842752;
Tel: +86-27-67842752
bCollege of Pharmacy, Wuhan University, Wuhan, 430072, China.
E-mail: 534801839@qq.com; Fax: +86-27-62754023; Tel: +86-27-68754629
†Electronic supplementary information (ESI) available. CCDC 918855 and
910500. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4dt00121d
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Scheme 1 Proposed selective N-methylation of amide bond of N-acyl-
hydrazone by an iron complex.
In this study, the selective methylation of N-2-hydroxybenz-
aldehyde acylhydrazone was developed based on the formation
of metal ion complexes. The effects of the metal ion
coordination in the methylation of N-2-hydroxybenzaldehyde
acylhydrazone were examined using methyl iodide as a methyl-
ating agent. It was found that metal complex formation
increases the N-methylation of amides and suppresses the
O-methylation of the hydroxyl group of the phenol. This
method can be applied to the selective methylation of amides
and avoids undesirable side reactions with the hydroxyl
group.2 The use of a protecting group on the hydroxyl was also
unnecessary.
Results and discussion
Synthesis
Scheme 2 The synthesis of the N-methyl-N’-2-hydroxybenzaldehyde
acylhydrazones (6a–6g).
The synthesis of N-2-hydroxybenzaldehyde acylhydrazones
(4a–4g) was carried out according to the procedures depicted
in Scheme 2. The compounds (4a–4g) were synthesized from
the corresponding acylhydrazines (3a–3g), which were
obtained from the esterification processing of carbonyl acids
(1a–1g), followed by a hydrazinolysis reaction using hydrazine
hydrate in ethanol. Thus, 4a–4g were prepared via acid-cata-
lyzed condensation of 3a–3g with the corresponding aromatic
aldehydes, as described in our previous work.22 The N-methyl-
N′-acylhydrazones were obtained from the corresponding
N-methylhydrazides by slowly adding a dilute solution of the
appropriate acid chloride as described in the literature.13,26,27
In the literature method, the N-methylhydrazides are not
readily available. We attempted to synthesize these N-methyl-
N′-2-hydroxybenzaldehyde acylhydrazones (6a–6g) by direct
methylation of the amide bonds of the corresponding N-2-
hydroxybenzaldehyde acylhydrazones (4a–4g) with potassium
carbonate using methyl iodide. The outcome of the experiment
was less than satisfactory; neither the amide N nor the phenol-
ate O was methylated. By analogy with the coordination mode
of the N-acylhydrazone ligands with various metal ions,24 we
predicted that the metal complex formation should increase
the N-methylation of the amides of 4a–4g. Various metal ions,
including Fe3+, Zn2+, Ni2+, Mn2+ and Co2+, were chosen to
investigate the stability and the solubility of metal complexes
of N-2-hydroxybenzaldehyde acylhydrazone in common
organic solvents. The results indicated that the complexes with
Fe3+ showed better stability and solubility in tetrahydrofuran
(THF) and N,N-dimethylformamide (DMF). Hence, the N-2-
hydroxybenzaldehyde acylhydrazones (4a–4g) were reacted
with FeCl3·6H2O, leading to the formation of metal complexes
5a–5g. Subsequently, the N-methyl-N′-2-hydroxybenzaldehyde
acylhydrazones (6a–6g) were synthesized by methylation of the
Fe(III)-N-2-hydroxybenzaldehyde
acylhydrazone
complexes
(5a–5g) with methyl iodide in the presence of potassium car-
bonate (Scheme 2). 6a–6g were obtained as solid materials by
removing the solvent under reduced pressure and recrystalliz-
ing from methanol. During the N-methylation process, the
phenol group could not be methylated because a coordinate
linkage between the oxygen atom of the phenol group and
Fe(III) was formed, which suppressed the O-methylation of the
phenol (see Fig. 1). The highly efficient N-methylation reaction
and the rapid and complete metal elimination step allowed us
to obtain the N-methyl-N′-2-hydroxybenzaldehyde acylhydra-
zones in high yields and excellent purity without time-consum-
ing chromatographic workup. We substituted Zn(OAc)2·2H2O
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Fig. 1 ORTEP diagram of the Fe(III) complex of N-(4-diethylamino-
2-hydroxy benzylidene)-benzohydrazide (5d).
for FeCl3·6H2O, and the soluble Zn(II)-N-2-hydroxybenzalde-
hyde acylhydrazone complex 5a′ could be obtained. The same
6a was synthesized by methylation of the Zn(II)-N-2-hydroxy-
benzaldehyde acylhydrazone complex 5a′.
Structural features
The N-2-hydroxybenzaldehyde acylhydrazones (4a–4c) present
two different sets of signals in the 1H NMR spectrum in deute-
rated chloroform or dimethyl sulfoxide, showing the presence
of two CO–NH bond-related syn and anti-periplanar confor-
mers.28 However, the N-methyl-N′-2-hydroxybenz-aldehyde acyl-
1
Fig. 2 1H NMR spectra of N-(4-diethylamino-2-hydroxybenzylidene)-
2-[4-(2-methylpropyl)phenyl]propane hydrazide (4a) (top) and
N-methyl-N’-(4-diethylamino-2-hydroxybenzylidene)-2-[4-(2-methyl-
propyl)phenyl]propane hydrazide (6a) (bottom).
hydrazones (6a–6c) present one set of signals in the H NMR
1
spectrum. Take 4a and 6a, for instance: their H NMR spectra
are shown in Fig. 2. In the spectrum of N-(4-diethyl amino-2-
hydroxybenzylidene)-2-[4-(2-methylpropyl)phenyl]propane
hydrazide (4a) (top in Fig. 2), the signal of the –OH proton
appears at 11.426 ppm and 10.968 ppm; that of the –NH
proton is at 11.241 ppm and 9.933 ppm; the NvCH proton
from 1630 cm−1 to 1660 cm−1 for the free ligands 4a–4g indi-
cate that the ligands are coordinated in the keto-form. The
CvN bond represented by the intense bands centered around
1600 cm−1 for the ligands 4a–4g was shifted to
1510–1520 cm−1, indicating that the imine N is coordinated to
the metal. The single crystal structure of 5d (see Fig. 1) con-
firms this coordination in the metal complexes 5a–5g.
1
appears at 8.154 ppm and 7.987 ppm, etc. As for the H NMR
spectrum of N-methyl-N′-(4-diethylamino-2-hydroxybenzyl-
idene)-2-[4-(2-methylpropyl)phenyl]propane hydrazide (6a)
1
(bottom in Fig. 2), one set of signals in the H NMR appears,
because the –NH proton is substituted by a methyl group. The
CO–NH bond-related syn and anti-periplanar conformation
rotation was restricted by N-methylation.
Single crystal structure of 5d
For the N-2-hydroxybenzaldehyde acylhydrazones (4a–4g),
the moderate broad bands centered at approximately Complex 5d [Fe(III)(C18N3H20O2)2]+Cl−(CH3OH) (H2O) crystal-
3400 cm−1 and 3200 cm−1 in the IR spectra are ascribed to the lizes in the triclinic space group P1. One water molecule and
ˉ
stretching vibrations of O–H and N–H, respectively. The three methanol molecules involved are free from co-ordination
characteristic stretching band of CvO at 1630–1660 cm−1 is an and captured in the lattice, and the three methanol molecules
indication that the keto-form is predominant in the solid state. are statistically disordered. Crystals of 5d were unstable
The CvN bond is represented by the intense bands centered outside of the mother liquor and lost guest solvent molecules
around 1600 cm−1. For the complexes 5a–5g, the absorption slowly. As shown in Fig. 1, the structure of complex 5d is com-
bands centered at approximately 3200 cm−1 due to N–H posed of Fe(III) and tridentate ligands 4d in a 1 : 2 ratio. The
stretching were still present, and the absorption bands cen- coordination geometry around each metal center is distorted
tered at approximately 3400 cm−1 may be ascribed to the O–H octahedral with two ligands bisecting each other at the central
stretching vibration of solvent molecules (H2O or CH3OH). The ferric ion, acting as tridentate ligands through the imine N,
moderate absorption bands at 1610 cm−1 are ascribed to the amide O and phenolate O atoms, which make two five-mem-
CvO stretching vibration, while the values found in the region bered and two six-membered chelating rings. With the elec-
7556 | Dalton Trans., 2014, 43, 7554–7560
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tron-withdrawing inductive effect of the neighboring imine-N-
metal and amide-O-metal coordinate linkages, the amide
could be deprotonated and methylated easily in the presence
of potassium carbonate. Meanwhile, the formation of the
phenolate-O-metal coordinate linkage efficiently suppressed
the O-methylation side reaction of the phenol. As a result, the
coordination of the N-acylhydrazone ligands with the metal
atom increases the specific N-methylation of the amide bond
and suppresses the O-methylation of the hydroxyl group of the
phenol (Scheme 1). Although the tridentate behavior is absol-
utely normal for acylhydrazone ligands, in 5d there are some
interesting hydrogen-bond motifs. As shown in Fig. 3 and
Table 2, each molecule of complex 5d is linked to the hydro-
gen-bonded structure through the ligand amide N–H groups,
Fig. 4 The H-bond network of N-methyl-N’-(4-diethylamino-2-hydro-
xylbenzylidene)-4-methoxy-benzohydrazide (6e). Hydrogen atoms are
intervening molecules of water O1W, methanol O1S, O2S and omitted for clarity.
Cl−1. The water molecule O1W acts as a single hydrogen-bonding
acceptor from ligand amide N–H and as a double hydrogen-
planar conformer in the solid state. In contrast with the N-2-
bonding donor to two methanol O1S and O2S. Two methanol
molecules O1S and O2S respectively act as a single hydrogen-
bonding acceptor from the water molecule O1W and a hydrogen-
bonding donor to Cl−1; Cl−1 acts as a quadruple hydrogen-
bonding acceptor from ligand amide N–H and three methanol
molecules O1S, O2S and O3S. Namely, one water molecule,
two methanol molecules and a Cl−1 form a hydrogen-bonding
cyclic tetramer, which interacts with two neighbouring
complexes 5d to form hydrogen-bonded 1-D chains by
intermolecular hydrogen-bonding interactions. The H-bond
network involving water, methanol, and the chloride ion
makes the crystal of 5d unstable outside of the mother liquor,
and it loses water and methanol molecules slowly.
hydroxybenzaldehyde acylhydrazones,28 the CO–NH bond-
related syn and anti-periplanar conformation rotation is
restricted in 6e, because the –NH proton is substituted by a
methyl group. Without the CO–NH bond rotating, the anti-
periplanar conformer disappears in solution. Therefore, one
set of signals appears in the 1H NMR spectra of 6a–6e (bottom
of Fig. 2).
Conclusions
A novel and efficient method for site-specific N-methylation of
N-2-hydroxybenzaldehyde acylhydrazones was developed. The
coordinate linkages of N-2-hydroxybenzaldehyde acylhydra-
zones with Fe3+/Zn2+ increase the specific N-methylation of the
amide bonds and suppress the O-methylation of the hydroxyl
group of the phenol. Consequently, the undesirable O-methyl-
ation side reaction was avoided. The chemospecific and quan-
titative N-methylation reaction and the rapid and complete
elimination of the metal allowed us to obtain N-methyl-N′-2-
hydroxybenzaldehyde-acylhydrazones in high yields and excel-
lent purity without time-consuming chromatographic workup.
A comparable effect was not observed in the methylation of
N-2-hydroxybenzaldehyde acylhydrazone without a metal ion.
These results demonstrated a synthetic technology that can
effectively promote the specific N-methylation of amides while
suppressing the O-methylation of the phenol groups without a
prior protecting step.
Single crystal structure of 6e
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-4-methoxy-
benzohydrazide (6e) crystallized in the monoclinic space group
P2(1)/c with one molecule of 6e in the asymmetric unit. As
shown in Fig. 4 and Table 2, a strong intramolecular hydrogen
bond existed between the N2 and O3 atoms [2.6501(17) Å], and
intermolecular hydrogen bonds existed between the C9 and O3
atoms [3.198(2) Å] and the C6 and O2 atoms [3.419(2) Å].
These intramolecular and intermolecular hydrogen bonds
caused 6e to adopt the fully extended E isomer and syn-peri-
Experimental
General methods
The starting materials were purchased from commercial
sources and used without further purification. The IR spectra
were recorded from KBr pellets in a range of 400–4000 cm−1
on a Perkin Elmer (Spectrum One) spectrometer. NMR spectra
were obtained on a 400 MHz spectrometer. Chemical shifts are
reported in δ relative to TMS. High-resolution mass spectra
Fig. 3 The H-bond network of complex 5d.
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(HRMS) were obtained using an ESI-QTOF mass spectrometer
(ESI). Elemental analyses (C, H, N) were carried out on a Vario
EL III. The melting points were determined on an XT-4 appar-
atus (uncorrected).
Table 2 Hydrogen bonds for 5d and 6e [Å and °]
D–H⋯A
d(D–H)
d(H⋯A)
d(D⋯A)
<(DHA)
5d
N(1)–H(1)⋯O(1W)
O(1W)–H(1W)⋯O(1S)
O(1W)–H(2W)⋯O(2S)
O(1S)–H(1S)⋯Cl(1)
O(2S)–H(2S)⋯Cl(1)
O(3S)–H(3S)⋯Cl(1)
N(4)–H(4)⋯Cl(1)
0.88
0.82
0.82
0.82
0.82
0.82
0.88
1.98
1.71
2.07
2.52
2.39
2.33
2.32
2.820(6)
2.48(3)
2.832(9)
3.342(17)
3.207(9)
3.146(17)
3.171(5)
160.0
155.9
155.3
175.5
179.5
177.5
163.5
Single-crystal X-ray diffraction measurements for 5d and 6e
were carried out on a Bruker Smart APEX CCD-based diffracto-
meter equipped with a graphite crystal monochromator for
data collection. The scattering intensity data were collected
using MoKα radiation (λ = 0.71073 Å). The structure was solved
by direct methods with SHELXS and refined with SHELXL.25
All non-hydrogen atoms were refined anisotropically and H
atoms isotropically with some restraints by full matrix least-
squares. Crystallographic data and experimental details for
structural analyses are summarized in Table 1. CCDC depo-
sition no. 918855 and 910500.
6e
O(3)–H(3A)⋯N(2)
C (6)–H(6)⋯O(2)
C (9)–H(9C)⋯O(3)
0.82
0.93
0.96
1.93
2.55
2.47
2.6501(17)
3.419(2)
3.198(2)
145.9
156.6
132.5
General procedure for the synthesis of the N-2-hydroxybenz-
aldehyde acylhydrazones (4a–4g). The N-2-hydroxybenzalde-
hyde acylhydrazones were prepared according to a previously
reported method.22 Briefly, to an ethanol solution (20 ml) of
the appropriate acylhydrazine (4.0 mmol) and 2-hydroxyben-
zaldehyde (4.0 mmol), a few drops of AcOH were added. The
mixture was heated at reflux for 1 h and then cooled to r.t. The
crystalline solid was collected by filtration, washed with cold
ethanol, and dried in air (see ESI†).
General procedure for the synthesis of the metal complexes
of N-2-hydroxybenzaldehyde acylhydrazones (5a–5g). Briefly, a
THF solution (20 ml) of the appropriate N-2-hydroxybenzalde-
hyde acylhydrazone (4.0 mmol) was added into an ethanol
solution (10 ml) of FeCl3·6H2O (1.07 g, 4.0 mmol). The mixture
was heated at reflux for 0.5 h, and then part of the solvent was
removed under vacuum, and the mixture was cooled to r.t. The
crystalline solid was collected by filtration, washed with cold
water, and dried in air. The melting points of the metal com-
plexes of the N-2-hydroxybenzaldehyde acylhydrazones (5a–5g)
exceed 300 °C. The elemental analyses and IR spectra of these
metal complexes were recorded (see ESI†).
General procedure for the synthesis of the N-methyl-N′-2-
hydroxybenzaldehyde-acylhydrazones
(6a–6g). 0.55
g
(4.0 mmol) potassium carbonate and 0.3 ml (4.0 mmol)
methyl iodide were added into a THF solution (10 ml) of the
appropriate metal complex of N-2-hydroxybenzaldehyde acyl-
hydrazone (5) (obtained from 4.0 mmol N-2-hydroxybenzalde-
hyde acylhydrazones (4)). The mixture was heated at reflux for
8–16 h. After the removal of the solid by hot filtration, rotary
evaporation was used to remove the solvent in the mother
liquor. Then, the solid was collected and recrystallized from
methanol, and
a crystalline solid, N-methyl-N′-2-hydroxy-
benzaldehyde acylhydrazone (6), was obtained.
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-2-[4-(2-
methylpropyl)phenyl]propane hydrazide (6a). The title com-
pound was obtained in a yield of 88.3%, 1.44 g, by the N-alkyl-
ation of metal complex 5a with methyl iodide, as a thin yellow
1
solid with mp 101–103 °C. H NMR (400 MHz, CDCl3) δ 10.52
Table 1 Crystallographic data for 5d and 6e
(s, 1H), 7.72 (s, 1H), 7.26 (d, 2H, J = 8.0 Hz), 7.06(d, 2H, J =
8.0 Hz), 7.01(d, 2H, J = 7.2 Hz), 6.23 (s, 2H), 4.50 (q, 1H, J =
6.8 Hz), 3.39 (s, 3H), 3.37 (q, 4H, J = 6.8 Hz), 2.40 (d, 2H, J = 7.2
Hz), 1.82 (m, 1H, J = 6.8 Hz), 1.50 (d, 3H, J = 6.8 Hz), 1.19 (t,
6H, J = 6.8 Hz), 0.90 (d, 6H, J = 6.8 Hz). 13C NMR (100 MHz,
CDCl3) δ 174.1, 159.2, 150.4, 144.5, 140.1, 138.5, 132.6, 129.3,
127.2, 106.8, 103.8, 98.2, 45.1, 44.5, 41.9, 30.1, 28.3, 22.4, 20.2,
12.6. IR (KBr) 3450 (w), 2967 (m), 2914 (m), 1660 (s), 1632 (vs),
1520 (m), 1405 (s). HRMS (ESI) m/z calcd for [C25H36N3O2]+
[M + H]+ 410.2802, found 410.2812. The same 6a was obtained
in a yield of 87.7%, 1.43 g, by the N-methylation of metal
complex 5a′ with methyl iodide.
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-2-(6-methoxy-
naphthyl)propane hydrazide (6b). The title compound was
obtained in a yield of 78.5%, 1.36 g, by the N-alkylation of
metal complex 5b with methyl iodide, as a thin yellow solid
with mp 134–136 °C. 1H NMR (400 MHz, CDCl3) δ 10.60 (s,
5d
6e
Empirical formula
Fw
Cryst syst
a(Å)
b(Å)
C37H46ClFeN6O6
762.10
Triclinic
C20H25N3O3
355.43
Monoclinic
10.3190(15)
15.155(2)
13.3440(19)
90.00
109.348(2)
90.00
1969.0(5)
P2(1)/c
12.311(4)
13.132(4)
14.299(5)
99.409(4)
108.611(4)
98.761(5)
2109.2(12)
ˉ
P1
2
1.200
c(Å)
α(°)
β(°)
γ(°)
V(Å3)
Space group
Z value
4
ρ(calcd) (g cm−3
Range of h, k, l
)
1.199
−14/14, −15/15,
−10/12, −18/18,
−16/14
−16/16
F(000)
802
760
Data/restraints/parameters
7284/1/483
1.61/25.01
0.468
3864/0/241
2.10/26.00
0.082
Θ min/max
μ(Mo Kα) (mm−1
T(K)
)
150(2)
296(2)
1H), 7.72 (s, 1H), 7.71 (m, 3H), 7.51 (dd, 1H, Jax = 8.4 Hz, Jbx
=
R1; wR2(I > 2σ(I))
R1; wR2(all)
Goodness-of-fit
0.0888; 0.2195
0.1335; 0.2463
0.986
0.0478; 0.1412
0.0607; 0.1585
1.022
1.6 Hz), 7.11 (m, 2H), 7.00 (d, 1H, J = 7.6 Hz), 6.23 (d, 1H, J =
8.0 Hz), 4.68 (q, 1H, J = 6.8 Hz), 3.91 (s, 3H), 3.43 (s, 3H),
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3.39 (q, 4H, J = 6.8 Hz), 1.60 (d, 3H, J = 6.8 Hz). 1.21 (t, 6H, CDCl3) δ 169.9, 159.1, 152.9, 150.4, 143.7, 139.7, 132.5, 130.2,
J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) δ 173.9, 159.2, 157.4, 106.6, 105.8, 103.6, 98.1, 60.9, 56.1, 44.4, 28.5, 12.6. IR (KBr)
150.4, 144.6, 136.6, 133.5, 132.6, 129.4, 129.0, 127.2, 126.7, 3447 (w), 2970 (m), 1627 (vs), 1587 (s), 1519 (m), 1465 (s), 1410
125.8, 118.7, 106.6, 105.5, 103.8, 97.9, 55.3, 44.5, 42.4, 28.3, (s). HRMS (ESI) m/z calcd for [C22H30N3O5]+ [M + H]+ 416.2180,
20.3, 12.7. IR (KBr) 3452 (w), 2971 (m), 2914 (m), 1654 (s), 1629 found 416.2190.
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-4-hydroxy-
benzohydrazide (6g). The title compound was obtained in a
yield of 76.9%, 1.05 g, by the N-alkylation of metal complex 5 g
(vs), 1518 (s), 1469 (s), 1403 (s). HRMS (ESI) m/z calcd for
[C26H32N3O3]+ [M + H]+ 434.2438, found 434.2435.
N-Methyl-N′-(2-hydroxybenzylidene)-2-(6-methoxynaphthyl)-
propane hydrazide (6c). The title compound was obtained in a with methyl iodide, as a colorless solid with mp 213–215 °C.
yield of 90.5%, 1.31 g, by the N-alkylation of metal complex 5c 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.92 (s, 1H), 8.03 (s,
with methyl iodide, as a white solid with mp 90–92 °C. 1H 1H), 7.40 (d, 2H, J = 8.4 Hz), 7.20 (d, 1H, J = 8.8 Hz), 6.80 (d,
NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 7.78 (s, 1H), 7.70 (t, 1H, J = 8.4 Hz), 6.22 (d, 1H, J = 8.8 Hz), 6.00 (s, 1H), 3.42 (s,
2H, J = 2.0 Hz), 7.68 (d, 1H, J = 2.0 Hz), 7.47 (dd, 2H, Jax
8.4 Hz, Jbx = 1.6 Hz), 7.28 (dd, 1H, Jax = 8.0 Hz, Jbx = 1.6 Hz), (100 MHz, DMSO) δ 169.6, 159.4, 158.7, 150.1, 143.3, 132.0,
7.18 (dd, 1H, Jax = 8.0 Hz, Jbx = 1.6 Hz), 7.09 (dd, 1H, Jax 130.8, 126.3, 115.0, 107.4, 104.0, 97.8, 44.2, 29.0, 12.9. IR (KBr)
=
3H), 3.30 (q, 4H, J = 7.2 Hz), 1.06 (t, 6H, J = 7.2 Hz). 13C NMR
=
8.8 Hz, Jbx = 2.4 Hz), 7.07 (m, 1H), 6.99 (d, 1H, J = 8.0 Hz), 6.89 3440 (m), 3292 (vs), 2971 (m), 1626 (vs), 1581 (s), 1516 (s).
(m, 1H, J = 2.0 Hz), 4.66 (q, 1H, J = 6.8 Hz), 3.88 (s, 3H), 3.44 (s, HRMS (ESI) m/z calcd for [C19H24N3O3]+ [M + H]+ 342.1812,
3H), 1.60 (d, 3H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) δ found 342.1813.
174.3, 157.7, 157.2, 143.5, 136.0, 133.6, 131.4, 131.3, 129.4,
129.0, 127.4, 126.4, 125.8, 119.7, 118.9, 117.9, 116.8, 105.5,
55.3, 42.6, 28.2, 20.4. IR (KBr) 3447 (w), 2968 (w), 2914 (w),
Acknowledgements
1674 (vs), 1605 (s), 1472 (s), 1399 (s). HRMS (ESI) m/z calcd for
[C22H23N2O3]+ [M + H]+ 363.1703, found 363.1699.
We thank the Key Project of the Natural Science Foundation of
Hubei Province, China (2008CDA067) and the Foundation of
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-benzohy-
drazide (6d). The title compound was obtained in a yield of
South-Central University for Nationalities.
88.6%, 1.15 g, by the N-alkylation of metal complex 5d with
methyl iodide, as a yellow solid with mp 97–98 °C. 1H NMR
(400 MHz, CDCl3) δ 9.81 (s, 1H), 7.77 (s, 1H), 7.54 (dd, 2H, Jax
=
7.6 Hz, Jbx = 1.6 Hz), 7.48 (m, 3H), 7.02 (d, 1H, J = 7.2 Hz), 6.20
(s, 1H), 6.08 (s, 1H), 3.55 (s, 3H), 3.31 (q, 4H, J = 6.8 Hz), 1.14
(t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) δ 170.7, 158.9,
150.3, 143.4, 135.5, 132.5, 130.2, 128.3, 127.8, 106.6, 103.6,
98.2, 44.5, 28.1, 12.6. IR (KBr) 3448 (w), 2973 (m), 1668 (s),
1627 (vs), 1521 (m), 1472 (m), 1404 (vs). HRMS (ESI) m/z calcd
for [C19H24N3O2]+ [M + H]+ 326.1863, found 326.1862.
Notes and references
1 A. E. Kummerle, M. Schmitt, S. V. S. Cardozo, C. Lugnier,
P. Villa, A. B. Lopes, N. C. Romeiro, H. Justiniano,
M. A. Martins, C. A. M. Fraga, J.-J. Bourguignon and
E. J. Barreiro, J. Med. Chem., 2012, 55, 7525.
2 H. K. R. Santhapuram, A. Datta, O. E. Hutt and G. I. Georg,
J. Org. Chem., 2008, 73, 4705.
3 E. Biron, J. Chatterjee, O. Ovadia, D. Langenegger,
J. Brueggen, D. Hoyer, H. A. Schmid, R. Jelinek, C. Gilon,
A. Hoffman and H. Kessler, Angew. Chem., Int. Ed., 2008,
47, 2595.
4 D. C. Pryde, G. N. Maw, S. Planken, M. Y. Platts,
V. Sanderson, M. Corless, A. Stobie, C. G. Barber,
R. Russell, L. Foster, L. Barker, C. Wayman, P. V. D. Graaf,
P. Stacey, D. Morren, C. Kohl, K. Beaumont, S. Coggon and
M. Tute, J. Med. Chem., 2006, 49, 4409.
5 Z. Che, S. Zhang, Y. Shao, L. Fan, H. Xu, X. Yu, X. Zhi,
X. Yao and R. Zhang, J. Agric. Food Chem., 2013, 61, 5696.
6 J. Chatterjee, C. Gilon, A. Hoffman and H. Kessler, Acc.
Chem. Res., 2008, 41, 1331.
7 J. Chatterjee, O. Ovadia, G. Zahn, L. Marinelli, A. Hoffman,
C. Gilon and H. Kessler, J. Med. Chem., 2007, 50, 5878.
8 J. Klages, C. Neubauer, M. Coles, H. Kessler and B. Luy,
ChemBioChem, 2005, 6, 1672.
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-4-methoxy-
benzohydrazide (6e). The title compound was obtained in a
yield of 91.1%, 1.29 g, by the N-alkylation of metal complex 5e
with methyl iodide, as a colorless solid with mp 110–111 °C.
1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.80 (s, 1H), 7.62
(m, 1H), 7.59 (m, 1H), 7.04 (d, 1H, J = 8.4 Hz), 6.98 (m, 1H),
6.96 (m, 1H), 6.23 (d, 1H, J = 8.0 Hz), 6.11 (s, 1H), 3.87 (s, 3H),
3.55 (s, 3H), 3.35 (q, 4H, J = 7.2 Hz), 1.17 (t, 6H, J = 7.2 Hz). 13
C
NMR (100 MHz, CDCl3) δ 170.2, 161.2, 158.9, 150.3, 143.3,
132.4, 130.4, 127.2, 113.4, 106.7, 103.7, 98.2, 55.2, 44.4, 28.5,
12.6. IR (KBr) 3446 (w), 2968 (m), 1653 (vs), 1627 (vs), 1517 (s),
1466 (s), 1404 (vs). HRMS (ESI) m/z calcd for [C20H26N3O3]+
[M + H]+ 356.1969, found 356.1977.
N-Methyl-N′-(4-diethylamino-2-hydroxybenzylidene)-3,4,5-tri-
methoxy-benzohydrazide (6f). The title compound was obtained
in a yield of 82.2%, 1.36 g, by the N-alkylation of metal
complex 5f with methyl iodide, as a gray solid with mp
130–132 °C. 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.81 (s,
1H), 7.04 (d, 1H, Jax = 8.8 Hz), 6.86 (s, 2H), 6.23 (d, 1H, J =
7.6 Hz), 6.10 (s, 1H), 3.94 (s, 3H), 3.89 (s, 6H), 3.56 (s, 3H), 3.36
(q, 4H, J = 7.2 Hz), 1.18(t, 6H, J = 7.2 Hz). 13C NMR (100 MHz,
9 O. Ovadia, S. Greenberg, J. Chatterjee, B. Laufer,
F. Opperer, H. Kessler, C. Gilon and A. Hoffman, Mol. Phar-
maceutics, 2011, 8, 479.
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Paper
Dalton Transactions
10 E. Belsito, M. L. D. Gioia, A. Greco, A. Leggio, A. Liguori, 20 C. Clavette, W. Gan, A. Bongers, T. Markiewicz,
F. Perri, C. Siciliano and M. C. Viscomi, J. Org. Chem., 2007,
72, 4798.
A. B. Toderian, S. I. Gorelsky and A. M. Beauchemin, J. Am.
Chem. Soc., 2012, 134, 16111.
11 M. Prashad, D. Har, B. Hu, H.-Y. Kim, O. Repic and 21 A. D. Hunt, I. Dion, N. D. Neves, S. Taing and
T. J. Blacklock, Org. Lett., 2003, 5, 125.
12 C. M. Crane and D. L. Boger, J. Med. Chem., 2009, 52, 1471.
13 L. Liu, M. H. Norman, M. Lee, N. Xi, A. Siegmund,
A. M. Beauchemin, J. Org. Chem., 2013, 78, 8847.
22 L. Wu, G. Qiu, H. Teng, Q. Zhu, S. Liang and X. Hu, Inorg.
Chim. Acta, 2007, 360, 3069.
A. A. Boezio, S. Booker, D. Choquette, N. D. DAngelo, 23 K. Yamauchi, T. Nakagima and M. Kinoshita, J. Org. Chem.,
J. Germain, K. Yang, Y. Yang, Y. Zhang, S. F. Bellon, 1980, 45, 3868.
D. A. Whittington, J.-C. Harmange, C. Dominguez, 24 L.-M. Wu, H.-B. Teng, X.-C. Feng, X.-B. Ke, Q.-F. Zhu,
T.-S. Kim and I. Dussault, J. Med. Chem., 2012, 55, 1868.
14 G. Lawton, C. J. Moody and C. J. Pearson, J. Chem. Soc.,
Perkin Trans. 1., 1987, 877.
J.-T. Su, W.-J. Xu and X.-M. Hu, Cryst. Growth Des., 2007, 7,
1337.
25 G. M. Sheldrick, Acta Cryst. A., 2008, 64, 112.
15 S. Liu, W. Gu, D. Lo, X.-Z. Ding, M. Ujiki, T. E. Adrian, 26 D. J. Benstead, A. N. Hulme, H. McNab and P. Wightb,
G. A. Soff and R. B. Silverman, J. Med. Chem., 2005, 48, 3630. SYNLETT, 2005, 10, 1571.
16 L. Aurelio, J. S. Box, R. T. C. Brownlee, A. B. Hughes and 27 Y. Xiong, J. Guo, M. R. Candelore, R. Liang, C. Miller,
M. M. Sleebs, J. Org. Chem., 2003, 68, 2652.
17 W. Gan, P. J. Moon, C. Clavette, N. D. Neves, T. Markiewicz,
A. B. Toderian and A. M. Beauchemin, Org. Lett., 2013, 15,
1890.
18 R. E. Dolle, M. C. Barden, P. E. Brennan, G. Ahmed, V. Tran
and D. M. Ho, Tetrahedron Lett., 1999, 40, 2907.
19 E. C. Taylor, R. J. Clemens and H. M. L. Davies, J. Org.
Chem., 1983, 48, 4567.
Q.
Dallas.
Yang,
G.
Jiang,
P.
E.
McCann,
S. A. Qureshi, X. Tong, S. S. Xu, J. Shang,
S. H. Vincent, L. M. Tota, M. J. Wright, X. Yang,
B. B. Zhang, J. R. Tata and E. R. Parmee, J. Med.
Chem., 2012, 55, 6137.
28 A. B. Lopes, E. Miguez, A. E. Kümmerle, V. M. Rumjanek,
C. A. M. Fraga and E. J. Barreiro, Molecules, 2013, 18,
11683.
7560 | Dalton Trans., 2014, 43, 7554–7560
This journal is © The Royal Society of Chemistry 2014