Acid Hydrazide: A Potential Reagent for the Synthesis of Semicarbazones

Article abstract of DOI:10.1055/s-0037-1609557

Complex semicarbazone derivatives were successfully synthesized from substituted semicarbazides in acidic ethanol upon heating in the presence of aldehyde. The reaction is functional group tolerant and chemoselective because no terminal hydrazine moiety i

Full text of DOI:10.1055/s-0037-1609557

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
A. R. Nath, W. A. Yehye
Paper
Synthesis
Acid Hydrazide: A Potential Reagent for the Synthesis of Semicar-
bazones
step 2
Amit R. Nath
OH
Wageeh A. Yehye*
G'
2 steps
Nanotechnology & Catalysis Research Centre (NANOCAT),
University of Malaya, Block 3A, Institute of Postgraduate
Studies, Kuala Lumpur 50603, Malaysia
N
HN
H
H
N
N
S
NH2
Step 1: Ar-NCO; toluene
G
O
wdabdoub@um.edu.my
O
acid hydrazide
Step 2: Ar-CHO; EtOH, HCl, 90 °C
step 1
28 examples semicarbazones
up to 95% yield
Functional group tolerant
Mild reaction conditions
NO terminal hydrazine moiety in semicarbazides
aryl groups can be changed by choice
Received: 06.05.2018
Accepted after revision: 15.06.2018
Published online: 07.08.2018
The well-known synthetic route to semicarbazones is a
reaction between semicarbazides and aldehyde in which
the semicarbazide compound is obtained by the treatment
of carbamate compounds with hydrazine, as seen in
Scheme 1.6 Unfortunately, formation of the desired semi-
carbazides has proved challenging and most are not com-
mercially available. Consequently, Asis et al. reported an-
other method to prepare semicarbazones involving the re-
action between appropriate monohydrazone and
isocyanate.7 However, this widely reported method3,7 is
limited by some functional groups such as ester or acyl
group. Semicarbazone derivatives bearing these functional
groups on an aromatic ring attached with N-4 (Scheme 1)
could not be synthesized easily because of the reactivity of
NH2 of urea, hydrazine and aromatic aldehyde monohydra-
zone towards some active functional groups such as ester,
DOI: 10.1055/s-0037-1609557; Art ID: ss-2018-z0312-op
Abstract Complex semicarbazone derivatives were successfully syn-
thesized from substituted semicarbazides in acidic ethanol upon heat-
ing in the presence of aldehyde. The reaction is functional group toler-
ant and chemoselective because no terminal hydrazine moiety is
present in the substituted semicarbazides. Thus, functional groups
such as esters and acetyls, which are prone to reaction with hydrazine,
can also be used in this reaction because the terminal hydrazine moiety
of the acid hydrazide was protected by aryl isocyanates in order to pre-
pare substituted semicarbazides. In addition, neither of the aryl groups
of semicarbazone are dependent on the starting materials (acid hydra-
zide) and can be changed upon demand. Thus, this reaction protocol
provides a simple and effective alternative for the preparation of a wide
variety of semicarbazones that could not be synthesized by utilizing
conventional methods.
Key words semicarbazones, substituted semicarbazides, acid hydra-
zide, hydrazine, nucleophilic substitution reaction
Method 1 (widely reported)
O
H
NH2NH2·H2O
NaCNO, glacial AcOH
NH2
The development of effective routes to nitrogen-bearing
molecules is a priority, considering that more than 90% of
pharmaceutical products have at least one nitrogen atom in
their framework and because one reaction out of six ac-
complished in the pharmaceutical industries is associated
with the construction of a carbon–nitrogen bond.1 Semicar-
bazone derivatives have attracted interest in both medici-
nal and pharmaceutical fields because of their broad spec-
trum of biological activities such as anticonvulsant, antitu-
mor, and anticancer properties.2,3 Its metal complexes also
exhibit significant activity against bacteria, fungi, and vi-
ruses, which extends the versatility of the application.4
Moreover, substituted semicarbazones can be used as a
platform chemical to prepare benzotriazepin compounds,
which are also an important class of drug because of their
psychostimulant, antidepressant, anorexigenic, and antihy-
pertensive properties.5
N
Ar
Ar
Ar
or NH2CONH2, py, reflux
NH2
carbamate
O
aldehyde
or ketone
O
H
N
4
H
N
1
N
Ar
HN
2
glacial AcOH
HN NH2
Ar'
semicarbazide
semicarbazone
Method 2, Asis et al. (1999)
O
H
N
4
benzene, r.t.
N
1
+
NCO
Ar
NH2
HN
2
N
Ar
Ar'
Ar'
aldehyde
monohydrazone
Scheme 1 Conventional methods for the preparation of semicarba-
zone
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
A. R. Nath, W. A. Yehye
Paper
Synthesis
oxadiazole, and other carbonyl compounds.8 Moreover, the
yield of most of the semicarbazones achieved by using such
synthetic techniques is poor. Garland et al. also reported the
preparation of semicarbazone and hydrazone derivatives
from common semicarbazones and hydrazones, respective-
ly, via imino-isocyanates, wherein various amines and ani-
lines were used as nucleophiles with hydrazones.9 Howev-
er, this protocol required a simple semicarbazone as start-
ing material; the N-4 part of the semicarbazone was only
replaced by amines or anilines as nucleophiles via nucleo-
philic substitution reaction to form a complex semicarba-
zone derivative.
Therefore, there remains a need to develop a robust syn-
thetic route to prepare new semicarbazones that offers bet-
ter functional group tolerance as well as chemoselectivity.
Hence, in this study we outlined a viable synthetic tech-
nique and developed a potential reaction route. An effective
and facile approach was adopted in this research to prepare
diverse semicarbazones containing ester or acetyl groups
on an aromatic ring attached at N-4. Acid hydrazide 3 was a
prerequisite precursor, which was prepared according to a
reported method showed in Scheme 2.10
Reaction between acid hydrazide and aryl isocyanates is
a straightforward reaction at room temperature that has
been reported by many researchers.11 Herein, we carried
out this reaction between prepared acid hydrazide 3 and
phenyl isocyanate at ambient temperature utilizing three
different solvents: toluene, dichloromethane (DCM), and
ethanol. Interestingly, although the reaction proceeded in
all the solvents, the reaction products started to form al-
most instantly in toluene whereas in dichloromethane and
ethanol it required around 10 and 20 minutes, respectively,
for the product solid to be visible. Thus, most of the reac-
tions were performed in toluene but a few aryl isocyanates
were insoluble in this media and, in this case, the reaction
was performed in DCM. The results of the reaction are sum-
marized in Scheme 3. The time required for the reaction to
reach completion was very short for semicarbazides substi-
tuted with phenyl isocyanate 4a, 4-fluorophenyl isocyanate
4b, 2,4-dichlorophenyl isocyanate 4c, m-tolyl isocyanate
4d, and naphthyl isocyanate 4g, but in the case of 4-acetyl-
phenyl isocyanate 4e and 3-(ethoxycarbonyl)phenyl isocya-
nate 4f, the required reaction time was noticeably longer (5
hours). This is possibly because of the nature of the substit-
uents on benzene ring of the aryl isocyanates, which deter-
mines their reactivity.
Arifin et al. (2014)
It was observed that the reaction time was markedly
shortened in the presence of a weakly electron-withdraw-
ing body such as F or Cl (4b, 4c) or even in the absence of
any substituents (4a and 4g) on the benzene or naphthyl
ring of the aryl isocyanate. Likewise, in the presence of
groups such as Ac and CO2Et, which moderately deactivate
the benzene ring, the reaction took approximately 5 hours
to complete. This can probably be attributed to the reso-
nance effect of the benzene ring bearing an acyl or ester
group. For further investigations, m-tolyl isocyanate was
utilized in the reaction to examine the effect of a ring acti-
vating group. Interestingly, this reaction also reached com-
pletion in a short time. However, the product yields of all
the substituted semicarbazide derivatives (≥ 90%) were
greatly increased.
With compounds 5a–g in hand, we performed the reac-
tion with substituted semicarbazides and benzaldehyde as
shown in Scheme 4. Best turnover was found at around
90 °C in the presence of a catalytic amount of HCl in ethanol
as solvent. The physical properties of the synthesized semi-
carbazones 7a–g, outlined in Scheme 4, show that N1-ben-
zylidene-N4-phenyl-semicarbazone (7a) was obtained with
90% yield along with (3,5-di-tert-butyl-4-hydroxybenzyl-
sulfanyl)acetic acid ethyl ester (8) by this method; Asis et al.
achieved 32% yield of 7a by using their reported method.7
Semicarbazones bearing 4-fluoro (7b), 2,4-dichloro (7c)
and 3-methyl (7d) substitution of the benzene ring at-
tached at N-4 provided about 90% yield. Gratifyingly, semi-
carbazones with N4-(3-ethoxycarbonylphenyl) (7f) and N4-
(4-acetylphenyl) (7e) moiety were also synthesized with
more than 80% yields.
L
OH
PTSA, toluene
reflux
L
L
MeOH, PTSA
reflux
HS
+
OH
S
O
OH
O
1
L
NH2NH2·H2O
OH
H
OMe
N
S
S
NH2
Hex, r.t.
O
O
L =
2
3
acid hydrazide
Scheme 2 Preparation of acid hydrazide 3
The newly employed synthetic technique involved the
preparation of substituted semicarbazides to protect the
free hydrazine moiety of the acid hydrazides. To our knowl-
edge, this is the first report of a reaction protocol for the
synthesis of semicarbazones from free hydrazine moiety
protected substituted semicarbazide. Functional groups
that are very reactive to free hydrazine could be used in this
reaction because no free hydrazine moiety was present in
the substituted semicarbazides. This is one of the main ad-
vantages of this reaction over the existing methods. In addi-
tion, the by-product of this reaction (3,5-di-tert-butyl-4-
hydroxybenzylsulfanyl)acetic acid ethyl ester proved the in-
volvement of the solvent in the reaction. A diverse range of
semicarbazone derivatives were synthesized to validate the
reaction protocol by using seven different substituted semi-
carbazides containing reactive functional groups such as
acetyl, ester etc.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
A. R. Nath, W. A. Yehye
Paper
Synthesis
OH
OH
toluene or CH2Cl2
r.t.
+
ArNCO
O
H
H
N
N
Ar
S
NH2
S
N
H
N
H
4a–g
O
O
3
5a–g
acid hydrazide
OH
OH
OH
Cl
F
O
O
O
H
N
H
N
H
N
S
N
H
N
H
S
N
N
H
S
N
N
H
H
H
O
Cl
O
O
5a
5b
5c
2 min, 99%d
2 min, 98%d
2 min, 98%e
OH
OH
OH
O
O
O
O
O
O
H
N
H
N
H
N
N
H
S
N
N
S
N
N
H
S
N
H
H
H
H
O
O
O
5d
5f
5e
5 h, 90%e
5 min, 95%d
5 h, 90%d
OH
O
H
N
S
N
N
H
H
O
5g
5 min, 90%d
Scheme 3 Evaluation of the reaction of substituted semicarbazides formation. a Reagents and conditions: 3 (3.12 mmol), 4a–g (3.12 mmol), room
temperature. b Reaction completion time. c Isolated yield. d toluene was used as solvent. e Dichloromethane was used as solvent.
In case of compound 7g, the N1-benzylidene-N4-naph-
thalene semicarbazone was isolated with 90% yield by using
the current method, whereas Asis et al.7 reported 20% yield
for this product and Azam et al.12 achieved 79% yields by
utilizing the broadly reported method. In the earlier report-
ed procedure the N4-phenyl ring of semicarbazone depend-
ed upon the phenyl amine that was taken as starting mate-
rials in the initial step. For instance, it was extremely trou-
m-anisaldehyde, 4-fluorobenzaldehyde, and cuminalde-
hyde to prepare semicarbazones containing different sub-
stituents on the N1-benzylidene ring under the same reac-
tion conditions; the results are outlined in Scheme 5.
To begin with, we endeavored to prepare semicarba-
zones with a N1-(4-fluorobenzylidene) ring. Gratifyingly,
the use of 4-fluorobenzaldehyde generated the expected
semicarbazones with better yields, reacting with all substi-
tuted semicarbazides (5a–g). Phenyl (7a1), 4-fluorophenyl
(7b1), and 2,4-dichlorophenyl (7c1) semicarbazone with N1-
(4-fluorobenzylidene) ring were obtained with 92, 95, and
90% yield, respectively.
blesome
to
obtain
N4-(alkoxycarbonylphenyl)
semicarbazones starting from the ester substituted phenyl
amine because of the high reactivity of hydrazine towards
the ester moiety in the second step.8
To examine the versatility of this method, three benzal-
dehydes having electron-donating and electron-withdraw-
ing groups were used. We carried out this reaction with
Though N1-(4-fluorobenzylidene)-N4-naphthyl-semi-
carbazone (7g1) was isolated with 80% yield by using the
earlier reported method,12 interestingly, yields increased to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
A. R. Nath, W. A. Yehye
Paper
Synthesis
OH
OH
EtOH, HCl
90 °C
+
+
O
N
H
H
N
Ar
O
CHO
HN
N
S
N
N
H
S
Ar
H
O
O
O
7a–g
5a–g
6a
8
N
N
N
HN
N
Cl
H
H
N
H
N
H
HN
N
HN
HN
N
O
O
O
O
F
Cl
7d, 90%
7a, 90%
7b, 90%
7c, 92%
N
N
O
N
H
H
H
HN
N
HN
N
HN
N
O
O
O
O
O
7g, 90%
7f, 80%
7e, 86%
Scheme 4 Evaluation of N1-benzylidene-N4-(substituted phenyl) semicarbazone. a Reagents and conditions: 5a–g (0.65 mmol), benzaldehyde 6a (0.65
mmol), HCl (1.6 mmol), ethanol (10 mL), 90 °C. b Isolated yield.
90% by the reaction of 2-(2-(3,5-di-tert-butyl-4-hydroxy-
benzylthio)acetyl)-N-naphthylhydrazinecarboamide (5g)
with 4-fluorobenzaldehyde.
fects the action of the nitrogen. Thus, formation of com-
pounds 5e and 5f took longer than the other substituted
semicarbazides.
We then assembled semicarbazones containing the N1-
(3-methoxybenzylidene)-ring by treating 3-methoxybenz-
aldehyde with pre-prepared substituted semicarbazides
5a–g. Phenyl (7a2), 4-fluoro (7b2), 2,4-dichloro (7c2), and
naphthyl (7g2) semicarbazones were accessed with around
90% yield; for the rest (7d2–7f2) turnovers were found to be
more than 80%. As noted in Scheme 5, the yield of com-
pounds 7e3 and 7f3, bearing a N1-(4-(2-isopropyl)ben-
zylidene) ring was around 70%, and for phenyl (7a3), 4-fluo-
rophenyl (7b3), 2,4-dichloro (7c3), m-tolyl (7d3) and naph-
thyl (7g3) semicarbazones were obtained with 80% yield.
The formation of substituted semicarbazide from acid
hydrazide and aryl isocyanate by a nucleophilic addition
mechanism is shown in Scheme 6. The hydrazine moiety of
acid hydrazide 3 might attack the carbonyl carbon of isocy-
anate, forming an intermediate with two positive charges.
In the subsequent step, the positively charged nitrogen
of the hydrazine part releases a proton to become a stable
ion and, on the other hand, the nitrogen of the aryl isocya-
nate moiety might be attracted by this roaming proton and
formed N–H bond. It could be anticipated from the different
reaction times that the resonance of the aromatic ring of
the aryl isocyanate bearing a different functional group af-
The observation that (3,5-di-tert-butyl-4-hydroxyben-
zylsulfanyl)acetic acid ethyl ester (8) was found as a reac-
tion product along with semicarbazones in every reaction,
indicates that solvent ethanol also participated in the reac-
tion as a substrate and this product 8 could be used in the
preparation of acid hydrazide 3 according to Scheme 7. Tak-
ing this into account, a plausible mechanism was drawn for
the formation of semicarbazones in the Scheme 7. Protona-
tion and nucleophilic attack of ethanol might occur at the
same carbonyl carbon of substituted semicarbazides then
the neighboring nitrogen might attack the protonated alde-
hyde, resulting in the formation of intermediate i. The latter
intermediate released compounds 8 and is again protonat-
ed. In the last step semicarbazone is formed by giving up a
hydronium ion.
The widely used semicarbazones preparation (Scheme
1) begins with reaction of aniline with the urea in the pres-
ence of pyridine or sodium cyanate in glacial acetic acid,
and results in the formation of a carbamate compound,
which is then reacted with hydrazine to give semicarbazide.
Condensation of semicarbazide with aromatic aldehyde in
the presence of glacial acetic acid provides semicarbazone.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
A. R. Nath, W. A. Yehye
Paper
Synthesis
OH
Ar'
N
EtOH, HCl
90 °C
+
8
H
Ar'CHO
+
HN
N
O
Ar
H
N
Ar
O
S
N
N
6b–e
H
H
7a1–g1
7a2–g2
7a3–g3
O
5a–g
F
F
F
F
F
F
N
Cl
N
O
N
H
N
N
N
H
H
H
H
N
H
HN
N
HN
N
HN
N
HN
HN
N
HN
N
O
O
O
O
O
O
O
Cl
F
7c1, 90%
7d1, 85%
7b1, 95%
7f1, 82%
7a1, 92%
7e1, 88%
O
OMe
F
OMe
OMe
OMe
OMe
N
H
N
N
H
N
H
Cl
N
H
N
HN
N
H
HN
N
H
HN
N
HN
N
HN
N
HN
N
O
O
O
O
O
O
Cl
F
O
7d2, 80%
7e2, 82%
7b2, 88%
7c2, 92%
7a2, 90%
7g1, 90%
OMe
OMe
N
N
Cl
N
H
O
N
H
N
N
H
H
HN
N
H
H
N
HN
N
HN
N
HN
N
HN
N
HN
O
O
O
O
O
O
O
Cl
F
7f2, 85%
7g2, 90%
7a3, 80%
7b3, 79%
7c3, 82%
7d3, 82%
N
H
N
O
O
N
HN
N
H
H
N
HN
N
HN
O
O
O
O
7e3, 70%
7f3, 75%
7g3, 85%
Scheme 5 Evaluation of semicarbazones from three different benzaldehydes. a Reagents and conditions: 5a–g (0.65 mmol), 6b–e (0.65 mmol), HCl (1.6
mmol), ethanol (10 mL), 90 °C. b Isolated yield. 7a1–g1 reaction performed with 4-fluorobenzaldehyde. 7a2–g2 reaction performed with m-anisalde-
hyde. 7a3–g3 reaction performed with cuminaldehyde.
Although this method is more common in the synthesis of
semicarbazones, unfortunately the use of aniline and a ter-
minal amino group in carbamate greatly limits its use for
the preparation of diverse semicarbazones. For instance,
certain carbamates bearing ester or acetyl group are very
difficult to synthesize because urea or cyanate molecules
are more susceptible to react with other reactive functional
groups instead of an amino group, which leads the unwant-
ed product instead of carbamate.7 In addition, formation of
semicarbazide in the second step by the reaction of carba-
mate bearing ester or acetyl group with hydrazine is more
problematic because hydrazine is very reactive to carbonyl
or ester groups. In another method (Scheme 1, Method 2),
aromatic aldehyde mono hydrazone, a key molecule in the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
A. R. Nath, W. A. Yehye
Paper
Synthesis
In conclusion, a variety of substituted semicarbazides
were easily accessed by a straightforward reaction of acid
hydrazide with aryl isocyanate bearing different substitu-
ents in order to protect the free hydrazine moiety of the
acid hydrazide. A nucleophilic substitution reaction of sub-
stituted semicarbazides with diverse substituted benzalde-
hyde has been established by which an extensive range of
semicarbazone compounds were synthesized with notable
yield. Since the hydrazine moiety is not free in the substi-
tuted semicarbazides, it can easily be converted into di-
verse complex semicarbazone compounds bearing different
reactive functional groups such as ester and acetyl groups.
Again, the obtained by-product 8 proved the involvement
of ethanol in the reaction, and this by-product could also be
used in the preparation of acid hydrazide, which would be
another interesting aspect of this method. Thus, this reac-
tion protocol pointedly offers a simple and robust alterna-
tive for the preparation of diverse semicarbazone deriva-
tives, resolving the limitations of conventional methods.
This reaction can also help to obtain distinct substitution
derivatives of semicarbazides forming more carbon–nitro-
gen bonds, the development of which is under way.
O
N
Ar
C
N
O
N
H
O
Ar
C
Ar
C
+
+
HN
L1
– H+
N
L1
L1
N
H
N
H
NH2
N
H
H
OH
H+
H
N
O
N
O
Ar
C
Ar
C
L1
=
+
HN
L1
HN
L1
N
N
H
S
H
O
Scheme 6 Proposed mechanism for the formation of substituted
semicarbazide
preparation of semicarbazone obtained from the reaction
of aldehyde with hydrazine, also experiences similar prob-
lems due to the unwanted reactions between hydrazine
molecule and other functional groups. Furthermore, the re-
action of hydrazone with isocyanate is not functional group
compatible. The above limitations are due to the presence
of the terminal amino group, which prevents both methods
from offering a wide variety of semicarbazones. Interest-
ingly, the problem has been solved in this work by protect-
ing the terminal hydrazine moiety of acid hydrazide with
aryl isocyanates, which led to substituted semicarbazides
bearing several active functional groups. Treatment of the
substituted semicarbazides with aldehyde in acidic ethanol
led to a substitution reaction in which the semicarbazones
and (3,5-di-tert-butyl-4-hydroxybenzylsulfanyl)acetic acid
ethyl ester (8) are generated in greater yields than those ob-
tained with existing methods.
All starting materials were of analytical grade, and double-distilled
water was used throughout the experiments. The solvents and re-
agents were supplied by Sigma–Aldrich and Merck, Malaysia and used
without further purification. Pre-coated silica gel plates (0.25 mm)
was utilized to observe the reaction by analytical thin-layer chroma-
tography and imagined by UV light. Column chromatography was
done on Silica Gel 60 (particle size: 0.040–0.063 mm). IR spectra were
recorded using FTIR-ATR of the solid samples. Melting points were
approximated. 600 MHz and 150 MHz NMR spectrometers were used
1
for H and 13C NMR analysis, respectively, and tetramethylsilane was
used as a reference. Chemical shifts (δ) are reported in ppm with re-
spect to the residual solvent peak (CHCl3, δ = 7.26 ppm; DMSO-d6, δ =
OH+
OH+
H
OH
Ar'
O
H
H
H+
H
H
H
H
N
N
N
N
N
N
L2
N
Ar
L2
N
Ar
OH
L2
N
Ar
– H+
O
+ H
H
H
N
H
H
O
O
N
C2H5
H
O
L2
N
Ar
O
H
O
C2H5
C2H5OH
H+
OH
Ar'
O
H
H
H
H
HO
Ar'
H2O
Ar'
H
H
H
H
HO
L2
H
H
N
H
H
N
N
N
N
N
N
N
Ar
N
N
Ar
+
N
Ar
Ar'
N
Ar
+
– H3O
H
H
H
O
O
O
O
C2H5
(i)
OH
L2
=
8
S
Scheme 7 Proposed mechanism for semicarbazone formation via substitution reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
A. R. Nath, W. A. Yehye
Paper
Synthesis
2.5 ppm for proton spectra; 13CDCl3, δ = 77.0 ppm; DMSO-d6, δ =
40 ppm for carbon spectra). High-resolution mass spectra were re-
corded with a time-of-flight Q-TOF LCMS system.
HRMS (Q-TOF): m/z [M + H]+ calcd for C24H31O3N3Cl2SNa+: 534.1355;
found: 534.1373.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(3-methyl-
Synthesis of 2-((3,5-Di-tert-butyl-4-hydroxybenzyl)thio)acetohy-
phenyl)hydrazinecarboxamide (5d)
drazide (3)
Yield: 1.35 g (95%); white solid; mp 106–108 °C.
2-((3,5-Di-tert-butyl-4-hydroxybenzyl)thio)acetohydrazide was syn-
thesized according to a previously described method.10 The com-
pound was solid and was stored at ambient temperature.
FTIR (ATR): 3361, 2916, 2853, 1607 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 9.80 (s, 1 H), 8.63 (s, 1 H), 8.10 (s,
1 H), 7.29 (s, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.08
(s, 2 H), 6.88 (s, 1 H), 6.79 (d, J = 7.2 Hz, 1 H), 3.78 (s, 2 H), 3.13 (s, 2 H),
2.26 (s, 3 H), 1.38 (s, 18 H).
Synthesis of Substituted Semicarbazides 5a–g (Gram Scale); Gen-
eral Procedure A
Acid hydrazide (1 g, 3.12 mmol) was stirred in toluene (20 mL) then
an equimolar amount of aryl isocyanate was introduced and the reac-
tion was monitored by TLC. All the substituted semicarbazides
formed white precipitates during the reaction, which were filtered
and washed several times with toluene. Dichloromethane (CH2Cl2)
was used for compounds 5c and 5e since 2,4-dichlorophhenylisocya-
nate and 4-acylphenylisocyanate are not soluble in toluene. Com-
pound structures were confirmed by IR, 13C NMR, 1H NMR and HRMS
analyses.
13C NMR (150 MHz, DMSO-d6): δ = 169.5, 155.7, 153.3, 139.9, 139.6,
138.3, 128.9, 128.9, 125.7, 123.1, 119.4, 116.1, 36.5, 34.9, 32.9, 30.8,
21.7.
HRMS (Q-TOF): m/z [M + Na]+ calcd for C25H35O3N3SNa+: 480.2291;
found: 480.2312.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(4-acetyl-
phenyl)hydrazinecarboxamide (5e)
Yield: 1.36 g (90%); white solid; mp 147–149 °C.
FTIR (ATR): 3368, 3092, 2918, 2850, 1613 cm–1
.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-phenylhy-
drazinecarboxamide (5a)
1H NMR (600 MHz, DMSO-d6): δ = 9.88 (s, 1 H), 9.83 (s, 1 H), 9.15 (s,
1 H), 8.33 (s, 1 H), 7.88 (d, J = 9 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.08
(s, 2 H), 6.88 (s, 1 H), 2.53 (s, 3 H), 1.38 (s, 18 H).
Yield: 1.42 g (99%); white solid; mp 128–130 °C.
FTIR (ATR): 3619, 3252, 2960, 1605 cm–1
.
13C NMR (150 MHz, DMSO-d6): δ = 196.8, 169.7, 153.3 144.8, 139.7,
131.0, 130.1, 129.9, 128.9, 125.7, 117.9, 36.5, 34.9, 32.9, 30.8, 26.8.
HRMS (Q-TOF): m/z [M + Na]+ calcd for C26H36O4N3SNa+: 486.2421;
found: 486.2435.
1H NMR (600 MHz, DMSO-d6): δ = 10.10 (s, 1 H), 9.67 (s, 1 H), 9.60 (b,
1 H), 7.45 (s, 2 H), 7.34 (t, J = 6 Hz, 1 H), 7.17 (t, J = 6 Hz, 1 H), 7.08 (s,
2 H), 6.90 (s, 1 H), 3.79 (s, 2 H), 3.17 (s, 2 H), 1.38 (s, 18 H).
13C NMR (150 MHz, DMSO-d6): δ = 181.4, 169.4, 153.3, 139.6, 139.5,
128.9, 128.6, 126.1, 125.7, 125.5, 36.7, 34.9, 33.4, 30.8.
HRMS (Q-TOF): m/z [M + Na]+ calcd for C24H33O3N3SNa+: 466.2140;
found: 466.2161.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(3-ethoxy-
carbonylphenyl)hydrazinecarboxamide (5f)
Yield: 1.45 g (90%); white solid; mp 157–159 °C.
FTIR (ATR): 3375, 3092, 2918, 2850 1620 cm–1
.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-4-(fluoro-
phenyl)hydrazinecarboxamide (5b)
1H NMR (600 MHz, DMSO-d6): δ = 9.83 (s, 1 H), 9.02 (s, 1 H), 8.23 (s,
1 H), 8.12 (s, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.41
(t, J = 7.8 Hz, 1 H), 6.87 (s, 1 H), 7.08 (s, 2 H), 4.32 (q, J = 7.2 Hz, 2 H),
1.38 (s, 18 H), 1.32 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 169.6, 166.2, 155.7, 153.3, 140.5,
140.4, 139.6, 130.8, 129.6, 129.5, 128.9, 125.7, 123.1, 119.4, 61.2, 36.6,
34.9, 32.9, 30.8, 14.7.
Yield: 1.41 g (98%); white solid; mp 160–162 °C.
FTIR (ATR): 3634, 3292, 2955, 1656 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 9.81 (s, 1 H), 8.76 (s, 1 H), 8.15 (s,
1 H), 7.47 (dd, J = 6 Hz, 2 H), 7.10 (t, J = 6 Hz, 2 H), 7.07 (s, 2 H), 6.89 (s,
1 H), 3.78 (s, 2 H), 3.12 (s, 2 H), 1.37 (s, 18 H).
.
13C NMR (150 MHz, DMSO-d6): δ = 169.5, 158.6, 157.1, 153.3, 136.4,
139.6, 128.9, 120.7, 115.6, 115.5, 36.5, 34.9, 32.9, 30.8.
HRMS (Q-TOF): m/z [M + Na]+ calcd for C27H37O5N3SNa+: 538.2346;
found: 538.2363.
HRMS (Q-TOF): m/z [M + Na]+ calcd for C24H32FO3N3SNa+: 484.2046;
found: 484.2051.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(1-naphth-
yl)hydrazinecarboxamide (5g)
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(2,4-di-
chlorophenyl)hydrazinecarboxamide (5c)
Yield: 1.42 g (92%); white solid; mp 123–125 °C.
FTIR (ATR): 3639, 3302, 2961, 1610 cm–1
.
Yields: 1.56 g (98%); white solid; mp 106–108 °C.
1H NMR (600 MHz, DMSO-d6): δ = 9.96 (s, 1 H), 8.79 (s, 1 H), 8.43 (s,
1 H), 8.06 (d, J = 12 Hz, 1 H), 7.92 (m, 1 H), 7.80 (br s, 1 H), 7.67 (d, J =
6 Hz, 1 H), 7.53 (m, 2 H), 7.46 (t, J = 6 Hz, 1 H), 7.08 (s, 2 H), 6.90 (s,
1 H), 3.80 (s, 2 H), 3.16 (s, 2 H), 1.36 (s, 18 H).
13C NMR (600 MHz, DMSO-d6): δ = 169.6, 156.4, 153.3, 139.7, 134.6,
134.2, 128.9, 128.7, 126.4, 126.2, 126.2, 125.7, 124.2, 122.4, 119.4,
36.6, 34.9, 32.9, 30.8.
FTIR (ATR): 3644, 3184, 2956, 1591 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.00 (s, 1 H), 8.91 (s, 1 H), 8.33 (b,
1 H), 8.11 (d, J = 6 Hz, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J = 3,
6 Hz, 2 H), 7.07 (s, 2 H), 6.89 (s, 1 H), 3.78 (s, 2 H), 3.13 (s, 2 H), 1.37 (s,
18 H).
13C NMR (150 MHz, DMSO-d6): δ = 169.4, 155.1, 153.3, 139.6, 135.5,
129.1, 128.8, 128.1, 126.8, 125.7, 123.3, 122.6, 36.5, 34.9, 32.6, 30.8.
HRMS (Q-TOF): m/z [M + H]+ calcd for C28H36O3N3S+: 494.2472; found:
494.2473.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
A. R. Nath, W. A. Yehye
Paper
Synthesis
Synthesis of Semicarbazone; General Procedure B
FT-IR (ATR): 3341, 3190, 3093, 2962, 2864, 1689.
1H NMR (600 MHz, DMSO-d6): δ = 11.17 (s, 1 H), 8.94 (s, 1 H), 8.19 (d,
J = 9 Hz, 1 H), 8.01 (s, 1 H), 7.73 (d, J = 7.2 Hz, 2 H), 7.70 (d, J = 2.4 Hz,
1 H), 7.47 (t, J = 7.2 Hz, 2 H), 7.45 (d, J = 2.4 Hz, 1 H), 7.43 (t, J = 3 Hz,
1 H).
13C NMR (150 MHz, DMSO-d6): δ = 152.7, 142.2, 134.9, 134.4, 130.3,
129.4, 129.1, 128.3, 127.4, 127.2, 124.3, 122.7.
Substituted semicarbazide (0.65 mmol) and an equimolar quantity of
aldehyde were mixed together in EtOH (ca. 10 mL) in a round-bottom
flask. The reaction mixture was then stirred at 90 °C for 4–5 hours in
the presence a catalytic amount of HCl (1.6 mmol) until the disap-
pearance of the starting materials spot was observed by thin-layer
chromatography. The reaction mixture was then warmed to ambient
temperature, and stirred for ca. 30 min. In most of the reactions, the
target compounds formed a solid precipitate during stirring at ambi-
ent temperature. The precipitate was filtered and washed with hex-
ane several times. The resultant products were then dried and either
recrystallized from hexane or purified by column chromatography.
On the other hand, when no precipitate was observed, the reaction
mixture was concentrated and residue was purified by column chro-
matography on silica gel with hexane/EtOAc mixture as eluent.
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H12Cl2N3O+: 308.0352;
found: 308.0364.
N1-(Benzylidene)-N4-(3-methylphenyl)semicarbazone (7d)
Yield: 148 mg (90%); white solid; mp 165–167 °C; Rf 0.54 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3356, 2916, 2853, 1628 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.73 (s, 1 H), 8.80 (s, 1 H), 7.96 (s,
1 H), 7.85 (d, J = 7.2 Hz, 2 H), 7.48 (s, 1 H), 7.47 (d, J = 6 Hz, 1 H), 7.43
(t, J = 6.6, 7.8 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 1 H),
6.84 (d, J = 7.8 Hz, 1 H), 2.30 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.5, 141.2, 139.4, 138.1, 134.9,
129.9, 129.1, 128.8, 127.5, 123.7, 120.8, 117.4, 21.6.
(3,5-Di-tert-butyl-4-hydroxybenzylsulfanyl)acetic Acid Ethyl Ester
(8)
Yield: 0.77–0.88 g (70–80%); brown gummy liquid; Rf 0.35 (hex-
ane/EtOAc, 1:1).
FTIR (ATR): 3564, 2955, 2914, 2873, 1728 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.03 (s, 1 H), 6.92 (s, 1 H), 4.10 (q,
J = 7.2 Hz, 2 H), 3.71 (s, 2 H), 3.18 (s, 2 H), 1.37 (s, 18 H), 1.20 (t, J =
7.2 Hz, 3 H).
HRMS (Q-TOF): m/z [M + H]+ calcd for C15H16N3O+: 254.1288; found:
254.1306.
13C NMR (150 MHz, DMSO-d6): δ = 170.5, 153.4, 139.7, 128.6, 125.7,
61.1, 36.3, 34.9, 32.7, 30.8, 14.5.
HRMS (Q-TOF): m/z [M + H]+ calcd for C19H31O3S+: 338.1916; found:
N1-(Benzylidene)-N4-(4-acetylphenyl)semicarbazone (7e)
Yield: 157 mg (86%); white solid; mp 180–182 °C; Rf 0.55 (hex-
ane/EtOAc, 2:1).
338.1912.
FTIR (ATR): 3361, 3200, 3099, 2957, 2857, 1693 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.93 (s, 1 H), 9.24 (s, 1 H), 7.99 (s,
1 H), 7.93 (d, J = 9 Hz, 2 H), 7.88 (d, J = 6 Hz, 2 H), 7.85 (d, 2 H), 7.45
(m, J = 7.8 Hz, 2 H), 7.42 (t, J = 7.2 Hz, 1 H), 2.54 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 196.9, 153.2, 144.2, 142.0, 134.7,
131.4, 130.1, 129.7, 129.1, 127.6, 119.1, 22.7.
N1-(Benzylidene)-N4-phenylsemicarbazone (7a)
Yield: 139.9 mg (90%); white solid; mp 178–180 °C; Rf 0.58 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3371, 3198, 3094, 2973, 2889, 1680 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.76 (s, 1 H), 8.91 (s, 1 H), 7.97 (s,
1 H), 7.87 (d, J = 6.6 Hz, 2 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.44 (t, J = 6.6,
7.8 Hz, 2 H), 7.40 (t, J = 7.2 Hz,1 H), 7.30 (t, J = 7.8, 8.4 Hz, 1 H),7.02 (t,
J = 7.2 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.5, 141.3, 139.5, 134.9, 129.9,
129.5, 128.9, 127.5, 122.9, 120.4.
HRMS (Q-TOF): m/z [M + H]+ calcd for C16H16N3O2+: 282.1237; found:
282.1248.
N1-(Benzylidene)-N4-(3-ethoxycarbonylphenyl)semicarbazone
(7f)
Yield: 161.8 mg (80%); white solid; mp 126–128 °C; Rf 0.59 (hex-
ane/EtOAc, 2:1).
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H14N3O+: 240.1131; found:
240.1149.
FTIR (ATR): 3361, 3193, 3058, 2917, 2850, 1633 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 9.18(s, 1 H), 10.84 (s, 1 H), 7.96 (d,
J = 6.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 8.34 (s, 1 H), 7.98 (s, 1 H), 7.45
(dt, J = 1.8, 8.4 Hz, 3 H), 7.41 (t, J = 6.6 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 2 H),
7.88 (d, J = 7.2 Hz, 2 H), 4.33(q, J = 7.2 Hz, 2 H), 1.33(t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 193.7, 166.3, 153.8, 153.6, 141.6,
140.1, 134.8, 129.9, 129.1, 127.7, 125.1, 123.6, 120.9, 61.2, 14.7.
N1-(Benzylidene)-N4-(4-fluorophenyl)semicarbazone (7b)
Yield: 150.4 mg (90%); white solid; mp 172–174 °C; Rf 0.52 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3377, 3193, 3102, 2958, 2832, 1680 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.75 (s, 1 H), 8.96 (s, 1 H), 7.96 (s,
1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.67 (dd, J = 3.6, 5.4 Hz, 2 H), 7.44 (t, J =
7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.14 (t, J = 9, 8.4 Hz, 2 H).
HRMS (Q-TOF): m/z M + H]+ calcd for C17H18N3O3+: 312.1343; found:
312.1357.
13C NMR (150 MHz, DMSO-d6): δ = 159.1, 157.5, 153.7, 141.3, 135.9,
N1-(Benzylidene)-N4-(1-naphthyl)semicarbazone (7g)
134.9, 129.9, 129.1, 127.5, 122.3, 115.3.
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H13FN3O+: 258.1037; found:
Yield: 169.2 mg (90%); white solid; mp 196–198 °C; Rf 0.43 (hex-
258.1052.
ane/EtOAc, 2:1).
FTIR (ATR): 3410, 3199, 3109, 2965, 2868, 1701 cm–1
.
N1-(Benzylidene)-N4-(2,4-dichlorophenyl)semicarbazone (7c)
Yield: 183.5 mg (92%); white solid; mp 222–223 °C; Rf 0.57 (hex-
ane/EtOAc, 2:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

I
A. R. Nath, W. A. Yehye
Paper
Synthesis
1H NMR (600 MHz, DMSO-d6): δ = 10.84 (s, 1 H), 9.19 (s, 1 H), 8.03 (s,
1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.88 (d, J =
7.2 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.57 (t, J =
6.6 Hz, 1 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.44 (t, J =
7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 154.4, 141.2, 135.0, 134.4, 134.2,
129.8, 129.1, 129.1, 128.6, 127.4, 126.4, 126.4, 126.1, 125.3, 122.9,
122.3.
1H NMR (600 MHz, DMSO-d6): δ = 10.72 (s, 1 H), 8.82 (s, 1 H), 7.95 (s,
1 H), 7.92 (dd, J = 3, 6 Hz, 2 H), 7.48 (d, J = 4.2 Hz, 1 H), 7.46 (s, 1 H),
7.26 (d, J = 9 Hz, 2 H), 7.18 (t, J = 7.8 Hz, 1 H), 6.84 (d, J = 7.2 Hz, 1 H),
2.29 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 162.4, 153.5, 140.0, 139.4, 138.1,
131.5 129.6, 128.8, 123.7, 120.9, 117.5, 115.9, 21.6.
HRMS (Q-TOF): m/z [M + H]+ calcd for C15H15N3FO+: 272.1194; found:
272.1209.
HRMS (Q-TOF): m/z [M + H]+ calcd for C18H16N3O+: 290.1288; found:
N1-(4-Fluorobenzylidene)-N4-(4-acetylphenyl)semicarbazone
290.1303.
(7e1)
N1-(4-Fluorobenzylidene)-N4-phenylsemicarbazone (7a1)
Yield: 171 mg (88%), white solid; mp 232–233 °C; Rf 0.55 (hex-
Yield: 153.8 mg (92%); white solid; mp 160–162 °C; Rf 0.45 (hex-
ane/EtOAc, 2:1).
ane/EtOAc, 2:1).
FTIR (ATR): 3377, 3193, 3102, 2958, 2832, 1680 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 10.75 (s, 1 H), 8.92 (s, 1 H), 7.95 (s,
1 H), 7.93 (d, J = 6, 2.4 Hz, 2 H), 7.65 (d, J = 7.8 Hz, 2 H), 7.30 (t, J =
7.8 Hz, 2 H), 7.27 (d, J = 9 Hz, 2 H), 7.03 (t, J = 7.2 Hz, 1 H).
FTIR (ATR): 3368, 3200, 3099, 2964, 2857, 1693 cm–1
.
.
1H NMR (600 MHz, DMSO-d6): δ = 10.93 (s, 1 H), 9.26 (s, 1 H), 7.98 (s,
1 H), 7.95 (d, J = 5.4 Hz, 2 H), 7.92 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 9 Hz,
2 H), 7.28 (t, J = 9 Hz, 2 H), 2.54 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 196.9, 164.1, 162.5, 153.2, 144.3,
140.9, 131.4, 131.3, 129.8, 129.7, 119.1, 116.1, 26.9.
13C NMR (150 MHz, DMSO-d6): δ = 162.4, 153.5, 140.1, 139.5, 131.5,
129.6, 128.9, 122.9, 120.4, 115.9.
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H13N3FO+: 258.1037; found:
HRMS (Q-TOF): m/z [M + H]+ calcd for C16H15N3FO2+: 300.1143; found:
300.1158.
258.1052.
N1-(4-Fluorobenzylidene)-N4-(3-ethoxycarbonylphenyl)semicar-
bazone (7f1)
N1-(4-Fluorobenzylidene)-N4-(4-fluorophenyl)semicarbazone
(7b1)
Yield: 175.4 mg (82%); white solid; mp 142–144 °C; Rf 0.58 (hex-
Yield: 169.8 mg (95%); white solid; mp 170–172 °C; Rf 0.57 (hex-
ane/EtOAc, 2:1).
ane/EtOAc, 2:1).
FTIR (ATR): 3368, 2917, 2850, 1633 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 10.74 (s, 1 H), 8.98 (s, 1 H), 7.95 (s,
1 H), 7.92 (d, J = 3, 5.4 Hz, 2 H), 7.66 (dd, J = 1.8, 5.4 Hz, 2 H), 7.26 (t, J =
9 Hz, 2 H), 7.14 (t, J = 9 Hz, 2 H).
FTIR (ATR): 3374, 3200, 3085, 2964, 1680 cm–1
.
.
1H NMR (600 MHz, DMSO-d6): δ = 10.82 (s, 1 H), 9.18 (s, 1 H), 7.96 (s,
1 H), 7.95 (d, J = 5.4 Hz, 2 H), 7.95 (d, J = 5.4 Hz, 1 H), 7.63 (d, J =
7.8 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.28 (d, J = 9 Hz, 2 H), 4.33 (q, J =
7.2 Hz, 2 H),1.33 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 162.4, 157.5, 153.7, 140.2, 135.9,
13C NMR (150 MHz, DMSO-d6): δ = 166.3, 164.1, 162.4, 153.6, 140.5
131.5, 129.6, 122.3, 115.9, 115.3.
131.5, 130.7, 129.8, 129.2, 125.1, 123.6, 120.8, 115.9, 61.2, 14.7.
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H11N3F2O+: 276.0943; found:
HRMS (Q-TOF): m/z [M + H]+ calcd for C17H17N3FO3+: 330.1248; found:
276.0961.
330.1264.
N1-(4-Fluorobenzylidene)-N4-(2,4-dichlorophenyl)semicarbazone
N1-(4-Fluorobenzylidene)-N4-(1-naphthyl)semicarbazone (7g1)
(7c1)
Yield: 179.7 mg (90%); white solid; mp 212–214 °C; Rf 0.39 (hex-
Yield: 190.2 mg (90%); white solid; mp 235–237 °C; Rf 0.54 (hex-
ane/EtOAc, 2:1).
ane/EtOAc, 2:1).
FTIR (ATR): 3341, 3197, 3086, 2962, 2831, 1689 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 11.17 (s, 1 H), 8.93 (s, 1 H), 8.16 (d,
J = 9.0 Hz, 1 H), 8.01 (s, 1 H), 7.81 (dd, J = 3, 6 Hz, 2 H), 7.70 (d, J =
2.4 Hz, 1 H), 7.43 (dd, J = 2.4, 6.6 Hz, 1 H), 7.30 (d, J = 9 Hz, 2 H).
FTIR (ATR): 3320, 3193, 2959, 2862, 1641 cm–1
.
.
1H NMR (600 MHz, DMSO-d6): δ = 10.85 (s, 1 H), 9.23 (s, 1 H), 8.01 (s,
1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.97 (m, J = 4.2 Hz, 1 H), 7.95 (d, J = 6 Hz,
1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 7.2 Hz, 1 H), 7.57 (t, J = 8.4 Hz,
2 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.28 (d, J = 9 Hz, 2 H).
13C NMR (150 MHz, DMSO-d6): δ = 162.6, 152.7, 141.1, 134.9, 131.1,
13C NMR (150 MHz, DMSO-d6): δ = 154.5, 139.9, 134.5, 134.2, 131.7,
129.3, 129.1, 128.3, 127.5, 124.6, 122.9, 116.5.
129.5, 129.2, 128.6, 126.3, 126.1, 125.4, 123.1, 122.71, 116.0.
HRMS (Q-TOF): m/z [M + H]+ calcd for C14H11N3Cl2FO+: 326.0258;
HRMS (Q-TOF): m/z [M + H]+ calcd for C18H15N3FO+: 308.1194; found:
found: 326.0263.
308.1208.
N1-(4-Fluorobenzylidene)-N4-(3-methylphenyl)semicarbazone
N1-(3-Methoxybenzylidene)-N4-phenylsemicarbazone (7a2)
(7d1)
Yield: 157.4 mg (90%); white solid; mp 130–132 °C; Rf 0.55 (hex-
Yield: 149.8 mg (85%); white solid; mp 152–154 °C; Rf 0.47 (hex-
ane/EtOAc, 2:1).
ane/EtOAc, 2:1).
FTIR (ATR): 3365, 2916, 2848, 1628 cm–1
FTIR (ATR): 3371, 3193, 3094, 2963, 2832, 1680 cm–1
.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
A. R. Nath, W. A. Yehye
Paper
Synthesis
1H NMR (600 MHz, DMSO-d6): δ = 10.74 (s, 1 H), 8.91 (s, 1 H), 7.93 (s,
1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.45 (s, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.32
(t, J = 7.8 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 2 H), 7.01 (t, J = 7.2 Hz, 1 H), 6.95
(dd, J = 1.2, 6.6 Hz, 1 H), 3.83 (s, 3 H).
1H NMR (600 MHz, DMSO-d6): δ = 10.96 (s, 1 H), 9.29 (s, 1 H), 7.96 (d,
J = 9 Hz, 1 H), 7.93 (d, J = 9 Hz, 2 H), 7.86 (d, J = 9 Hz, 2 H), 7.48 (s, 1 H),
7.39 (d, J = 7.2 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 6.99 (dd, J = 1.2, 6.6 Hz,
1 H), 3.83 (s, 3 H), 2.53 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.02, 153.5, 141.2, 139.5, 136.3,
13C NMR (150 MHz, DMSO-d6): δ = 196.9, 160.0, 153.3, 144.3, 141.9,
130.2, 128.9, 123.0, 120.4, 115.9, 115.9, 112.1, 55.7.
136.1, 131.4, 130.2, 129.7, 120.5, 119.1, 116.0, 112.3, 55.7, 26.9.
HRMS (Q-TOF): m/z [M + H]+ calcd for C15H16N3O2+: 270.1237; found:
HRMS (Q-TOF): m/z [M + H]+ calcd for C17H18N3O3+: 312.1343; found:
270.1252.
312.1355.
N1-(3-Methoxybenzylidene)-N4-(4-fluorophenyl)semicarbazone
N1-(3-Methoxybenzylidene)-N4-(3-ethoxycarbonylphenyl)semi-
(7b2)
carbazone (7f2)
Yield: 164.2 mg (88%); white solid; mp 125–127 °C; Rf 0.41 (hex-
Yield: 188.5 mg (85%); white solid; mp 104–106 °C; Rf 0.57 (hex-
ane/EtOAc, 2:1).
ane/EtOAc, 2:1).
FTIR (ATR): 3314, 3240, 2998, 2957, 2836, 1673 cm–1
.
FTIR (ATR): 3394, 3193, 3092, 2978, 1687 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.76 (s, 1 H), 9.00 (s, 1 H), 7.93 (s,
1 H), 7.67 (dd, J = 1.8, 5.4 Hz, 2 H), 7.45 (s, 1 H), 7.36 (d, J = 7.2 Hz,
1 H), 7.34 (t, J = 7.2 Hz, 1 H), 7.14 (t, J = 9 Hz, 2 H), 6.97 (dd, J = 1.2,
6.6 Hz, 1 H), 3.82 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.01, 157.6, 153.7, 141.2, 136.3,
135.9, 130.1, 122.4, 120.4, 115.9, 115.3, 112.1, 55.7.
1H NMR (600 MHz, DMSO-d6): δ = 10.85 (s, 1 H), 9.21 (s, 1 H), 8.35 (s,
1 H), 7.95 (s, 1 H), 7.93 (d, J = 1.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.48
(s, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.35 (t, J =
7.8 Hz, 1 H), 6.98 (dd, J = 1.8, 6.6 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 3.83
(s, 3 H),1.33 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 166.3, 160.0, 153.6, 141.5, 140.0,
136.2, 130.7, 130.1, 129.2, 125.1, 123.6, 120.9, 120.4, 115.8, 112.3,
61.2, 55.7, 14.7.
HRMS (Q-TOF): m/z [M + H]+ calcd for C15H15N3FO2+: 288.1143; found:
288.1155.
HRMS (Q-TOF): m/z [M + H]+ calcd for C18H20N3O4+: 342.1448; found:
N1-(3-Methoxybenzylidene)-N4-(2,4-dichlorophenyl)semicarba-
342.1458.
zone (7c2)
N1-(3-Methoxybenzylidene)-N4-(1-naphthyl)semicarbazone (7g2)
Yield: 201.6 mg (92%); white solid; mp 200–201 °C; Rf 0.61 (hex-
ane/EtOAc, 2:1).
Yield: 186.7 mg (90%); white solid; mp 194–196 °C; Rf 0.57 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3360, 3203, 3099, 2969, 2831, 1696 cm–1
.
FTIR (ATR): 3380, 3187, 3091, 2959, 2868, 1683 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.76 (s, 1 H), 9.00 (s, 1 H), 8.21 (d,
J = 9 Hz, 1 H), 7.98 (s, 1 H), 7.70 (s, 1 H), 7.44 (dd, J = 2.4, 6 Hz, 1 H),
7.37 (t, J = 7.8 Hz, 1 H), 7.33 (s, 1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.00 (dd,
J = 2.4, 5.4 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.0, 152.9, 141.9, 135.9, 134.9,
130.5, 129.1, 128.4, 127.4, 124.2, 122.6, 120.1, 116.6, 111.1, 55.5.
HRMS (Q-TOF): m/z [M + H]+ calcd for C15H14N3Cl2O2+: 338.0458;
found: 338.0464.
N1-(3-Methoxybenzylidene)-N4-(3-methylphenyl)semicarbazone
(7d2)
1H NMR (600 MHz, DMSO-d6): δ = 10.88 (s, 1 H), 9.24 (s, 1 H), 8.00 (d,
J = 3.6 Hz, 1 H), 7.99 (s, 1 H), 7.97 (d, J = 7.2 Hz, 1 H), 7.79 (d, J = 8.4 Hz,
1 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.56 (dt, J = 1.2, 2.4 Hz, 2 H), 7.53 (t, J =
7.2 Hz, 1 H), 7.52 (s, 1 H), 7.36 (d, J = 5.4 Hz, 1 H), 7.34 (t, J = 7.8 Hz,
1 H), 6.98 (d, J = 2.4, 6.6 Hz, 1 H), 3.83 (s, 3 H), 2.53 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.1, 154.4, 141.0, 136.4, 134.4,
134.2, 130.2, 129.1, 128.6, 126.4, 126.3, 126.1, 125.3, 122.3, 120.4,
116.1, 111.4, 55.7.
HRMS (Q-TOF): m/z [M + H]+ calcd for C19H18N3O2+: 320.1394; found:
320.1402.
Yield: 147.2 mg (80%); white solid; mp 142–144 °C; Rf 0.50 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3371, 3193, 3083, 2952, 2837, 1680 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 10.75 (s, 1 H), 8.85 (s, 1 H), 7.93 (s,
1 H), 7.50 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.44 (s, 1 H), 7.37 (d, J =
7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 1 H), 6.97 (dd,
J = 1.2, 6.6 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 3.82 (s, 3 H), 2.30 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.0, 153.5, 141.1, 139.4, 138.1,
136.3, 130.2, 128.7, 123.7, 120.9, 120.3, 117.6, 115.8, 112.1, 55.7, 21.7.
HRMS (Q-TOF): m/z [M + H]+ calcd for C16H18N3O2+: 284.1394; found:
284.1407.
N1-(4-Isopropylbenzylidene)-N4-phenylsemicarbazone (7a3)
.
Yield: 146.2 mg (80%); white solid; mp 140–142 °C; Rf 0.65 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3377, 3193, 3089, 2952, 2863, 1675 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.67 (s, 1 H), 8.85 (s, 1 H), 7.93 (s,
1 H), 7.76 (d, J = 7.8 Hz, 2 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.30 (d, J =
7.8 Hz, 2 H), 7.30 (t, J = 7.8 Hz, 2 H), 7.02 (t, J = 7.8 Hz, 1 H), 2.93 (m, J =
7.2 Hz, 1 H), 1.22 (d, J = 7.2 Hz, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.5, 150.4, 141.3, 139.5, 132.6,
128.9, 127.6, 127.0, 122.9, 120.3, 33.8, 24.2.
HRMS (Q-TOF): m/z [M + H]+ calcd for C17H20N3O+: 282.1601; found:
282.1615.
N1-(3-Methoxybenzylidene)-N4-(4-acetylphenyl)semicarbazone
(7e2)
Yield: 157.3 mg (82%); white solid; mp 129–131 °C; Rf 0.52 (hex-
ane/EtOAc, 2:1).
N1-(4-Isopropylbenzylidene)-N4-(4-fluorophenyl)semicarbazone
(7b3)
FTIR (ATR): 3354, 3185, 3082, 2951, 2837, 1693 cm–1
.
Yield: 153.6 mg (79%); white solid; mp 114–116 °C; Rf 0.50 (hex-
ane/EtOAc, 2:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
A. R. Nath, W. A. Yehye
Paper
Synthesis
FTIR (ATR): 3368, 2917, 2850, 1633 cm–1
.
FTIR (ATR): 3448, 3193, 3092, 2957, 2884, 1664 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.70 (s, 1 H), 8.94 (s, 1 H), 7.93 (s,
1 H), 7.76 (d, J = 7.8 Hz, 2 H), 7.67 (dd, J = 4.8 Hz, 2 H), 7.30 (d, J =
7.8 Hz, 2 H), 7.14 (t, J = 9 Hz, 2 H), 2.92 (m, J = 7.2 Hz, 1 H), 1.22 (d, J =
6.6 Hz, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 157.4, 153.7, 150.4, 141.4, 135.9,
132.6, 127.6, 127.0, 122.2, 115.3, 33.8, 24.2.
1H NMR (600 MHz, DMSO-d6): δ = 10.75 (s, 1 H), 9.13 (s, 1 H), 8.33 (s,
1 H), 7.96 (s, 1 H), 7.95 (s, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.62 (d, J =
7.8 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2 H), 4.33 (q, J =
7.2 Hz, 2 H), 2.92 (m, J =6.6 Hz, 1 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.22 (d, J =
7.2 Hz, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 166.3, 153.6, 150.5, 141.7, 140.1,
132.5, 130.7, 129.2, 127.7, 127.0, 124.9, 123.5, 120.9, 61.2, 33.8, 24.2,
14.7.
HRMS (Q-TOF): m/z [M + H]+ calcd for C17H19N3FO+: 300.1507; found:
300.1519.
HRMS (Q-TOF): m/z [M + H]+ calcd for C20H24N3O3+: 354.1812; found:
N1-(4-Isopropylbenzylidene)-N4-(2,4-dichlorophenyl)semicarba-
354.1824.
zone (7c3)
N1-(4-Isopropylbenzylidene)-N4-(1-naphthyl)semicarbazone (7g3)
Yield: 186 mg (82%); white solid; mp 191–193 °C; Rf 0.55 (hex-
ane/EtOAc, 2:1).
Yield: 183 mg (85%); white solid; mp 171–173 °C; Rf 0.72 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3350, 3195, 3110, 2960, 1689 cm–1
FTIR (ATR): 3350, 3193, 3115, 2959, 1689 cm–1
.
.
1H NMR (600 MHz, DMSO-d6): δ = 11.11 (s, 1 H), 8.94 (s, 1 H), 8.24 (d,
J = 12 Hz, 1 H), 7.98 (s, 1 H), 7.70 (d, J = 2.4 Hz, 1 H), 7.64 (d, J = 7.8 Hz,
2 H), 7.42 (dd, J = 2.4, 6.6 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 2.92 (m, J =
6.6 Hz, 1 H), 1.21 (d, J = 6.6 Hz, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 152.7, 151.0, 142.3, 134.9, 132.1,
129.0, 128.4, 127.4, 127.2, 124.0, 122.3, 33.8, 24.2.
1H NMR (600 MHz, DMSO-d6): δ = 10.85 (s, 1 H), 9.18 (s, 1 H), 8.01 (s,
1 H), 8.00 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 2 H), 7.74
(d, J = 8.4 Hz, 1 H), 7.58 (t, J = 8.4 Hz, 1 H), 7.54 (t, J = 7.2 Hz, 1 H), 7.51
(t, J = 7.8 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2 H), 2.92 (m, J = 6 Hz, 1 H), 1.22
(d, J = 6 Hz, 6 H).
13C NMR (600 MHz, DMSO-d6): δ = 154.4, 150.4, 141.3, 134.4, 134.2,
132.7, 128.7, 128.6, 127.4, 127.1, 126.4, 126.1, 125.1, 122.8, 121.8,
33.8, 24.2.
HRMS (Q-TOF): m/z [M + H]+ calcd for C17H18N3Cl2O+: 350.0821;
found: 350.0831.
HRMS (Q-TOF): m/z [M + H]+ calcd for C21H22N3O+: 332.1752; found:
332.1773.
N1-(4-Isopropylbenzylidene)-N4-(3-methylphenyl)semicarbazone
(7d3)
Yield: 157.3 mg (82%); white solid; mp 146–148 °C; Rf 0.68 (hex-
ane/EtOAc, 2:1).
FTIR (ATR): 3377, 3188, 3089, 2958, 2853, 1680 cm–1
Funding Information
.
1H NMR (600 MHz, DMSO-d6): δ = 10.67 (s, 1 H), 8.77 (s, 1 H), 7.92 (s,
1 H), 7.75 (d, J = 7.8 Hz, 2 H), 7.49 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.29
(d, J = 8.4 Hz, 2 H), 7.17 (t, J = 7.8 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 2.90
(m, J = 7.2 Hz, 1 H), 2.30 (s, 3 H), 1.22 (d, J = 7.2 Hz, 6 H).
Grand Challenge (GC001C-14AET), PPP Grant PG208-2015B provided
by the University of Malaya and Ministry of Higher Education, Malay-
sia (MOHE).
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13C NMR (150 MHz, DMSO-d6): δ = 153.5, 150.4, 141.3, 139.4, 138.1,
132.6, 128.8, 127.5, 127.0, 123.6, 120.7, 117.4, 33.8, 24.2, 21.6.
Acknowledgment
HRMS (Q-TOF): m/z [M + H]+ calcd for C18H22N3O+: 296.1757; found:
296.1770.
The authors would like to thank the University of Malaya and the
Ministry of Higher Education, Malaysia for their cordial support in
completing this work. We also thank Dr. Rauful Alam (Postdoc Re-
searcher, University of Pennsylvania) for his valuable suggestions.
N1-(4-Isopropylbenzylidene)-N4-(4-acetylphenyl)semicarbazone
(7e3)
Yield: 147.1 mg (70%); white solid; mp 136–138 °C; Rf 0.48 (hex-
ane/EtOAc, 2:1).
Supporting Information
FTIR (ATR): 3365, 3180, 3018, 2964, 2857, 1673 cm–1
.
Supporting information for this article is available online at
1H NMR (600 MHz, DMSO-d6): δ = 10.90 (s, 1 H), 9.25(s, 1 H), 8.00 (s,
1 H), 7.98 (d, J = 9 Hz, 2 H), 7.91 (d, J = 9 Hz, 1 H), 7.83 (d, J = 8.4 Hz,
1 H), 7.37 (d, J = 8.4 Hz, 2 H), 2.98 (m, J = 6.6 Hz, 1 H), 2.59 (s, 3 H),
1.28 (d, J = 7.2 Hz, 6 H).
https://doi.org/10.1055/s-0037-1609557.
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References
13C NMR (150 MHz, DMSO-d6): δ = 197.0, 153.2, 150.6, 144.3, 140.1,
132.4, 131.4, 129.7), 127.7, 127.0, 119.1, 33.8, 26.8, 24.2.
HRMS (Q-TOF): m/z [M + H]+ calcd for C19H22N3O2: 324.1707; found:
324.1718.
(1) (a) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
Dev. 2005, 9, 253. (b) Roveda, J.-G.; Clavette, C.; Hunt, A. D.;
Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc.
2009, 131, 8740.
(2) (a) Pandeya, S. N. Acta Pharm. 2012, 62, 263. (b) Liu, Z.; Wu, S.;
Wang, Y.; Li, R.; Wang, J.; Wang, L.; Zhao, Y.; Gong, P. Eur. J. Med.
Chem. 2014, 87, 782. (c) Yogeeswari, P.; Sriram, D.; Pandeya, S.
N.; Stables, J. P. Farmaco 2004, 59, 609. (d) Dimmock, J.; Baker,
N1-(4-Isopropylbenzylidene)-N4-(3-ethoxycarbonylphenyl)semi-
carbazone (7f3)
Yield: 172.2 mg (75%); white solid; mp 120 °C; Rf 0.57 (hexane/EtOAc,
2:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
A. R. Nath, W. A. Yehye
Paper
Synthesis
G. Epilepsia 1994, 35, 648. (e) Mishra, V.; Pandeya, S. N.;
Pannecouque, C.; Witvrouw, M.; De Clercq, E. Arch. Pharm.
2002, 335, 183.
S. N.; Yogeeswari, P.; Stables, J. P. Eur. J. Med. Chem. 2000, 35,
879. (d) Jafri, L.; Ansari, F. L.; Jamil, M.; Kalsoom, S.; Qureishi, S.;
Mirza, B. Chem. Biol. Drug Des. 2012, 79, 950.
(3) (a) Yogeeswari, P.; Sriram, D.; Veena, V.; Kavya, R.; Rakhra, K.;
Ragavendran, J. V.; Mehta, S.; Thirumurugan, R.; Stables, J.
Biomed. Pharmacother. 2005, 59, 51. (b) Yogeeswari, P.;
Thirumurugan, R.; Kavya, R.; Samuel, J. S.; Stables, J.; Sriram, D.
Eur. J. Med. Chem. 2004, 39, 729.
(7) Asís, S. E.; Bruno, A. M.; Martínez, A. R.; Sevilla, M. a. V.; Gaozza,
C. H.; Romano, A. M.; Coussio, J. D.; Ciccia, G. Farmaco 1999, 54,
517.
(8) Saravanan, S.; Sridharan, V.; Muthusubramanian, S. Synth.
Commun. 2006, 36, 849.
(4) (a) Pelosi, G.; Bisceglie, F.; Bignami, F.; Ronzi, P.; Schiavone, P.;
Re, M. C.; Casoli, C.; Pilotti, E. J. Med. Chem. 2010, 53, 8765.
(b) Noblía, P.; Baran, E. J.; Otero, L.; Draper, P.; Cerecetto, H.;
González, M.; Piro, O. E.; Castellano, E. E.; Inohara, T.; Adachi, Y.
Eur. J. Inorg. Chem. 2004, 322.
(5) Douchez, A.; Lubell, W. D. Org. Lett. 2015, 17, 6046.
(6) (a) Yogeeswari, P.; Sriram, D.; Thirumurugan, R.; Raghavendran,
J. V.; Sudhan, K.; Pavana, R. K.; Stables, J. J. Med. Chem. 2005, 48,
6202. (b) Jung, M. E.; Chamberlain, B. T.; Ho, C.-L. C.; Gillespie, E.
J.; Bradley, K. A. ACS Med. Chem. Lett. 2014, 5, 363. (c) Pandeya,
(9) Garland, K.; Gan, W.; Depatie-Sicard, C.; Beauchemin, A. M. Org.
Lett. 2013, 15, 4074.
(10) Ariffin, A.; Rahman, N. A.; Yehye, W. A.; Alhadi, A. A.; Kadir, F. A.
Eur. J. Med. Chem. 2014, 87, 564.
(11) (a) Majumdar, P.; Pati, A.; Patra, M.; Behera, R. K.; Behera, A. K.
Chem. Rev. 2014, 114, 2942. (b) Drummond, J. T.; Johnson, G.
J. Heterocycl. Chem. 1988, 25, 1123.
(12) Azam, F.; El-gnidi, B. A.; Alkskas, I. A. Eur. J. Med. Chem. 2010, 45,
2817.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L