Facile synthesis and in-vitro antimalarial activity of novel α-hydroxy hydrazonates

Article abstract of DOI:10.1002/ardp.201000346

A series of previously unreported α-hydroxy hydrazonates were synthesized and tested for their antimalarial properties. Structure optimization of the antiplasmodially active α-hydroxy hydrazonate III furnished derivatives with strong in-vitro antimalarial

Full text of DOI:10.1002/ardp.201000346

Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
755
Full Paper
Facile Synthesis and In-Vitro Antimalarial Activity of Novel
a-Hydroxy Hydrazonates
Mehdi Khankischpur1, Finn K. Hansen1, Ronald Meurer1, Tobias Mauz1, Baerbel Bergmann2,
Rolf D. Walter2, and Detlef Geffken1
1 Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Hamburg, Germany
2 Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
A series of previously unreported a-hydroxy hydrazonates were synthesized and tested for their
antimalarial properties. Structure optimization of the antiplasmodially active a-hydroxy hydrazonate
III furnished derivatives with strong in-vitro antimalarial activity against 3D7 strains of Plasmodium
falciparum with IC50 values lower than 2.0 mM.
Keywords: Antimalarial activity / Hydrazonates / Plasmodium falciparum / a-Hydroxy imidates
Received: November 11, 2010; Revised: December 23, 2010; Accepted: January 11, 2011
DOI 10.1002/ardp.201000346
Introduction
As shown in Fig. 2, the lead III was modified by altering the
aryl group at C2 (A), by replacing the methyl group (B) or the
hydroxyl group at the C2 atom (E) by hydrogen, by altering
the ethyl residue of the hydrazonate functionality (C) and by
replacement of the carbazone-ester group by a (thio)semicar-
bazone functionality (D). Toward this goal, efficient synthetic
methods for the envisioned novel compounds had to be
developed which are disclosed in the next section.
Apart from their utility in synthetic heterocyclic chemistry
[1–3], the esters of hydrazonoic acids, namely hydrazonates,
are of interest for medicinal chemists because of their versa-
tile biological properties. For instance, hydrazonates have
been found to exhibit anthelmintic, antifungal and anti-
inflammatory activities [4–6] and contribute as toxophores/
pharmacophores to bactericides or herbicides [7, 8].
So far, the antimalarial activity of hydrazonates has not yet Results and discussion
been reported, whereas aroylhydrazones (I) and thiosemicar-
bazones (II) (Fig. 1), structurally related to hydrazonates, have
been shown to possess potent antimalarial activity (IC50 for I:
5 mM, for II: 4 mM, Plasmodium falciparum 3D7 strains) as
reported by Walcourt and coworkers [9]. Over the past years,
we have studied the synthesis and reactivity of a-hydroxy
imidates (2) and a-hydroxy hydrazonates (4) as precursors for
the preparation of various 5- and 6-membered functionalized
heterocycles [10, 11]. Because of the finding that compound
III, originally developed in our group as a building block for
novel heterocycles, displayed strong in vitro activity against
3D7 strains of P. falciparum (IC50 ¼ 1.5 mM), we became inter-
ested in the structure-activity relationship of III, and disclose
here the synthesis and antiplasmodial evaluation of a variety
of analogues of our lead compound III (Fig. 2).
Chemistry
We started the preparation of a-hydroxy hydrazonates 4 from
cyanohydrins 1, which were accessible according to litera-
ture [12]. Next, cyanohydrins 1 were converted by a Pinner
reaction [13] into the corresponding a-hydroxy imidate
hydrochlorides 2. Since the reaction of 2 with carbazates
was found to afford amidrazones as by-products and a-
hydroxy hydrazonates 4 in only moderate yields, we devel-
oped a more efficient route as demonstrated in Scheme 1.
Treatment of imidate hydrochlorides 2 with a saturated
solution of hydrogen sulfide in dry dichloromethane-
pyridine [14] furnished smoothly a-hydroxy thiocarboxylic
O-esters 3 in 78–88% yield. Subsequent reaction of 3 with
carbazates afforded the desired a-hydroxy hydrazonates 4
in 67–87% yields as mixtures of E- and Z-isomers (see
Experimental section). The synthesis of a-hydroxy hydrazo-
nates 5 and 6 was accomplished by reaction of 3 with semi-
carbazides or thiosemicarbazides [15] in ethyl acetate as a
solvent, respectively.
Correspondence: Detlef Geffken, Institute of Pharmacy, University of
Hamburg, Bundesstr. 45, D-20146 Hamburg, Germany.
E-mail: geffken@chemie.uni-hamburg.de
Fax: þ49 40 42838 6573
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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M. Khankischpur et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Figure 1. Known antiplasmodials I and II, and title compounds 4–6.
Scheme 1. Synthesis of a-hydroxy hydrazonates 4–6. For details
see experimental part.
Biological activity
The in-vitro antiplasmodial activity of compounds 4–6 was
evaluated by the 8-[3H]-hypoxanthine incorporation assay
according to the method of Desjardins using the chloroquine
sensitive strain 3D7 of Plasmodium falciparum [16]. IC50 values
as well as the inhibition of parasite growth at 5 mM have
been determined. Pyrimethamine (Pyr) was used as reference
compound (Tables 1, 2).
The in-vitro studies revealed that derivatives of 4 with a
dihalogenated phenyl ring or a naphthyl residue at C2
exhibit strongest antiplasmodial activity within the set of
prepared compounds. Replacement of the C-2 methyl group
by hydrogen caused a significant decrease of activity, whereas
an ethyl residue at C-2 increased antiplasmodial activity as
highlighted in Fig. 3. Compound 7 lacking a hydroxyl group
at C-2 was almost devoid of antiplasmodial activity, hence
indicating the importance of the a-hydroxyl group for anti-
plasmodial activity. Complete loss of antimalarial activity
was observed for benzyl- and phenethyl imidates 4n and
4o, whereas the alkyl imidates 4a, 4l displayed remarkable
activity. Modification of the carbazone-ester moiety generally
caused a decrease of antiplasmodial activity, with the excep-
tion of the semicarbazone 5d, exhibiting an IC50 value of
0.85 mM.
Experimental
Melting points were determined on an Electrothermal 9100
apparatus. Elemental analyses were carried out with
a
Heraeus CHN-O-Rapid instrument. IR spectra were recorded on
an ATI Genesis Series FT-IR. 1H-NMR (400 MHz) and 13C-NMR
Figure 2. Structure modifications of the lead III.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Table 1. Inhibition of P. falciparum growth.
Facile Synthesis and In-Vitro Antimalarial Activity . . .
757
(100 MHz) spectra were recorded on a Bruker AMX 400 spec-
trometer using tetramethylsilane as internal standard and
DMSO-d6 or CDCl3 as solvents. Mass spectra were recorded on
a Micromass VG 70-250S mass spectrometer (HRFAB).
Entry
R1
R2
R3
R4
5 mM [%]a)
4a
4b
4c
4d
4e
4f
3,4-Cl-Ph
4-Cl-3-Me-Ph
2-Naphthyl
2-Naphthyl
1-Naphthyl
3,4-Cl-Ph
Me
Me
Me
Me
H
Et
Et
Et
Et
Et
t-Bu
Me
Et
t-Bu
t-Bu
t-Bu
Et
Bn
Me
75
72
83
56
7
12
66
19
19
75
4
Chemistry
General procedure for the synthesis of compounds 2a–t
To a solution of the corresponding cyanohydrin 1 (30 mmol) in
anhydrous Et2O (50 mL), 1.2 equivalents of the appropriate anhy-
drous alcohol and HCl gas were added at 08C according to the
Pinner synthesis [13]. After 5 d at ꢀ108C, the solid imidate
hydrochlorides 2a–t were isolated by filtration, suspended in
anhydrous Et2O and filtered. The structures of imidate hydro-
chlorides 2a–t were confirmed by IR spectroscopy. All imidate
hydrochlorides were used for the synthesis of compounds 3
without further purification.
H
Et
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
3,4-Cl-Ph
4-CH3-Ph
3,4-CH3-Ph
4-Cl-Ph
4-Cl-Ph
3,4-Cl-Ph
3,4-Cl-Ph
3,4-Cl-Ph
3,4-Cl-Ph
3-Br-4-F-Ph
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
3,4-Cl-Ph
3,4-Cl-Ph
3,4-Cl-Ph
3,4-Cl-Ph
2-Naphthyl
3,4-Cl-Ph
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Et
Et
4-Cl-Bn
Me
n-Pr
Bn
C2H4Ph
Et
Me
n-Pr
Bn
C2H4Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
t-Bu
t-Bu
t-Bu
t-Bu
Et
Et
Et
Et
Et
Me
66
43
0
0
70
76
85
0
0
40
5
14
75
19
15
0
7
5
80
Ethyl 2-hydroxy-2-(4-methylphenyl)propanimidoate
hydrochloride 2a
Colorless solid, yield: 88%, mp: 89.78C; IR nmax (KBr) cmꢀ1: 1638.
4s
4t
5a
5b
5c
5d
5e
5f
5g
6a
7b)
Pyrc)
Ethyl 2-(4-chlorophenyl)-2-hydroxypropanimidoate
hydrochloride 2b
Bn
OBn
Me
Colorless solid, yield: 79%; mp: 103.88C; IR nmax (KBr) cmꢀ1: 1638.
Bn
4-Me-Bn
4-Cl-Bn
Et
4-Chlorobenzyl 2-(4-chlorophenyl)-2-hydroxypropan-
imidoate hydrochloride 2c
Colorless solid, yield: 84%; mp: 85.78C; IR nmax (KBr) cmꢀ1
1643.
:
t-Bu
a)
Ethyl 2-(3,4-dimethylphenyl)-2-hydroxypropan-imidoate
hydrochloride 2d
Mean values of four independent determinations.
Compound 7 represents 4f without hydroxyl group at C2.
Pyr ¼ pyrimethamine
b)
c)
Colorless solid, yield: 77%; mp: 82.58C; IR nmax (KBr) cmꢀ1: 1650.
Ethyl 2-(3,4-dichlorophenyl)-2-hydroxypropanimidoate
hydrochloride 2e
Colorless solid, yield: 83%; mp: 106.78C; IR nmax (KBr) cmꢀ1: 1654.
Table 2. IC50 values of selected compounds 4 and 5 against
P. falciparum
Methyl 2-(3,4-dichlorophenyl)-2-hydroxypropanimidoate
hydrochloride 2f
Compound
Activity against P. falciparum
Colorless solid, yield: 91%; mp: 98.18C; IR nmax (KBr) cmꢀ1: 1651.
IC50 [mM]
na)
SEMb)
4a
4b
4c
4d
4g
4j
4.9
5.1
2.0
4.4
2.9
5.0
2.5
1.5
1.1
0.6
6.2
0.85
0.07
4
4
4
4
4
4
4
4
4
4
4
6
8
0.7
0.7
0.1
1.57
1.14
0.4
0.79
0.2
0.45
0.1
2.54
0.23
0.03
Propyl 2-(3,4-dichlorophenyl)-2-hydroxypropanimidoate
hydrochloride 2g
Colorless solid, yield: 74%; mp: 93.88C; IR nmax (KBr) cmꢀ1
1653.
:
:
:
Benzyl 2-(3,4-dichlorophenyl)-2-hydroxypropanimidoate
hydrochloride 2h
4l
4p
4q
4r
5a
5d
Pyrc)
Colorless solid, yield: 81%; mp: 82.78C; IR nmax (KBr) cmꢀ1
1653.
2-Phenylethyl 2-(3,4-dichlorophenyl)-2-hydroxy-
propanimidoate hydrochloride 2i
n ¼ number of determinations. SEM ¼ standard error of
Colorless solid, yield: 79%; mp: 111.88C; IR nmax (KBr) cmꢀ1
1653.
a)
b)
c)
the mean. Pyr ¼ pyrimethamine.
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M. Khankischpur et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Ethyl 2-(3-bromo-4-fluorophenyl)-2-hydroxypropan-
imidoate hydrochloride 2j
Colorless solid, yield: 81%; mp: 99.48C; IR nmax (KBr) cmꢀ1: 1647.
Ethyl 2-(4-chloro-3-methylphenyl)-2-hydroxypropan-
imidoate hydrochloride 2k
Colorless solid, yield: 85%; mp: 101.38C; IR nmax (KBr) cmꢀ1: 1651.
Ethyl 2-hydroxy-2-(naphthalen-2-yl)propanimidoate
hydrochloride 2l
Colorless solid, yield: 88%; mp: 119.28C; IR nmax (KBr) cmꢀ1: 1652.
Methyl 2-hydroxy-2-(naphthalen-2-yl)propanimidoate
hydrochloride 2m
Colorless solid, yield: 85%; mp: 109.58C; IR nmax (KBr) cmꢀ1: 1651.
Propyl 2-hydroxy-2-(naphthalen-2-yl)propanimidoate
hydrochloride 2n
Colorless solid, yield: 77%; mp: 93.58C; IR nmax (KBr) cmꢀ1: 1652.
Benzyl 2-hydroxy-2-(naphthalen-2-yl)propanimidoate
hydrochloride 2o
Colorless solid, yield: 86%; mp: 85.78C; IR nmax (KBr) cmꢀ1: 1654.
Figure 3. Structure-activity relationships on the example of 4a.
Inhibition of P. falciparum growth at 5 mM.
2-Phenylethyl 2-hydroxy-2-(naphthalen-2-yl)propan-
imidoate hydrochloride 2p
Colorless solid, yield: 83%; mp: 119.38C; IR nmax (KBr) cmꢀ1: 1659.
O-Ethyl 2-hydroxy-2-(4-methylphenyl)propanethioate 3a
Pale yellow oil, yield: 87%; IR nmax (KBr) cmꢀ1: 3387 (OH), 1279
Ethyl 2-hydroxy-2-(naphthalen-1-yl)ethanimidoate
hydrochloride 2q
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.37 (t, J ¼ 7.0 Hz, 3H),
–
3
Colorless solid, yield: 86%; mp: 125.28C; IR nmax (KBr) cmꢀ1: 1647.
1.80 (s, 3H), 2.32 (s, 3H), 4.43–4.63 (m, 2H), 4.80 (s, 1H), 7.16–7.46
(m, 4H); 13C-NMR (400 MHz, CDCl3), d (ppm): 13.4, 21.0, 27.2,
70.6, 80.2, 125.5, 128.8, 137.2, 141.1, 222.2; HRFAB-
MS C12H16O2S [MþH]þ: Calcd. 225.0949; found 225.0959.
Ethyl 2-(3,4-dichlorophenyl)-2-hydroxyethanimidoate
hydrochloride 2r
Colorless solid, yield: 63%; mp: 114.48C; IR nmax (KBr) cmꢀ1: 1652.
O-Ethyl 2-(4-chlorophenyl)-2-hydroxypropanethioate 3b
Pale yellow oil, yield: 87%; IR nmax (KBr) cmꢀ1: 3377 (OH), 1285
1
Ethyl 2-(3,4-dichlorophenyl)-2-hydroxybutanimidoate
hydrochloride 2s
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.37 (t, J ¼ 7.0 Hz, 3H),
–
3
1.80 (s, 3H), 4.44–4.64 (m, 2H), 4.81 (s, 1H), 7.26–7.52 (m, 4H);
13C-NMR (400 MHz, CDCl3), d (ppm): 13.4, 27.4, 70.9, 79.9, 127.2,
128.2, 133.6, 142.5, 225.5; HRFAB-MS C11H13ClO2S [MþH]þ: Calcd.
245.0403; found 245.0400.
Colorless solid, yield: 67%; mp: 103.18C; IR nmax (KBr) cmꢀ1: 1654.
Benzyl 2-hydroxy-2-methylpropanimidoate hydrochloride
2t
Colorless solid, yield: 66%; mp: 66.78C; IR nmax (KBr) cmꢀ1: 1651.
O-(4-Chlorobenzyl) 2-(4-chlorophenyl)-2-hydroxy-
propanethioate 3c
Colorless solid, yield: 78%; mp: 48.78C, IR nmax (KBr) cmꢀ1: 3400
General procedure for the synthesis of compounds 3a–p
20 mmol of the appropriate imidate hydrochlorides 2 were added
to a saturated solution of hydrogen sulfide in anhydrous dichloro-
methane/pyridine (100 mL) at 58C and the reaction mixture was
stirred at room temperature for 1 h. The solvent was evaporated,
diethylether (40 mL) was added and the mixture was washed with
1 M hydrochloric acid (3 ꢁ 20 mL). The organic layer was dried
with MgSO4, filtered and the solvent was evaporated. The remain-
ing residues were purified by filtration through a short silica gel
column (5 cm) with CH2Cl2/hexane (3:1) as an eluent to give
compounds 3a–p as pale yellow oils or solids.
1
–
(OH), 1278 (C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.81, 5.39–
–
3
5.50 (q, 2H), 7.12–7.48 (m, 8H); 13C-NMR (400 MHz, CDCl3),
d (ppm): 27.6, 75.5, 80.5, 127.6, 128.7, 129.4, 129.9, 132.8,
134.1, 135.3, 142.5, 226.3; HRFAB-MS C16H14Cl2O2S [MþH]þ:
Calcd. 341.0170; found 341.0183.
O-Ethyl 2-(3,4-dimethylphenyl)-2-hydroxypropane-thioate
3d
Colorless solid, yield: 82%; mp: 43.18C, IR nmax (KBr) cmꢀ1: 3379
(OH), 1275 (C S); 1H-NMR (400 MHz, CDCl3), d (ppm): 1.39
–
–
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Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Facile Synthesis and In-Vitro Antimalarial Activity . . .
759
(t, J ¼ 7.1 Hz, 3H), 1.79 (s, 3H), 2.26 (s, 6H), 4.44–4.65 (m, 2H), 4.73
(s, 1H), 7.07–7.33 (m, 3H); 13C-NMR (400 MHz, CDCl3), d (ppm):
13.6, 29.0, 69.5, 81.1, 122.9, 126.6, 129.2, 135.3, 135.8, 142.5,
227.0; HRFAB-MS C13H18O2S [MþH]þ: Calcd. 239.1106; found
239.1099.
13C-NMR (400 MHz, CDCl3),
d
(ppm): 13.9, 27.6, 71.0, 79.3,
2
2
108.6 (d, JC,F ¼ 21.4 Hz), 115.7 (d, JC,F ¼ 22.1 Hz), 126.6
3
3
4
(d, JC,F ¼ 7.6 Hz), 131.1 (d, JC,F ¼ 13.0 Hz), 141.3 (d, JC,F ¼ 3.8 Hz),
1
158.4 (d, JC,F ¼ 244.9 Hz), 225.3; HRFAB-MS C11H12BrFO2S [MþH]þ:
Calcd. 306.9804; found 306.9816.
O-Ethyl 2-(3,4-dichlorophenyl)-2-hydroxypropane-thioate
3e
O-Ethyl 2-hydroxy-2-(naphthalen-2-yl)propanethioate 3k
Pale yellow oil, yield: 88%; IR nmax (KBr) cmꢀ1: 3383 (OH), 1283
1
Colorless solid, yield: 86%; mp: 36.18C, IR nmax (KBr) cmꢀ1: 3364
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.35 (t, J ¼ 7.1 Hz, 3H),
–
3
(OH), 1281 (C S); 1H-NMR (400 MHz, CDCl3), d (ppm): 1.39
1.93 (s, 3H), 4.42–4.64 (m, 2H), 4.93 (s, 1H), 7.43–8.06 (m, 7H);
13C-NMR (400 MHz, CDCl3), d (ppm): 13.4, 27.6, 70.8, 80.4, 123.8,
124.5, 126.1, 127.5, 127.7, 127.7, 128.4, 132.7, 133.0, 141.2,
226.8; HRFAB-MS C15H16O2S [MþH]þ: Calcd. 261.0949; found
261.0938.
–
–
(t, J ¼ 7.0 Hz, 3H), 1.79 (s, 3H), 4.46–4.65 (m, 2H), 4.84 (s, 1H),
7.39–7.67 (m, 3H); 13C-NMR (400 MHz, CDCl3), d (ppm): 13.4, 27.5,
71.1, 79.5, 125.3, 128.0, 130.0, 131.8, 132.3, 144.1, 226.7; HRFAB-
MS C11H12Cl2O2S [MþH]þ: Calcd. 279.0013; found 279.0008.
O-Methyl 2-hydroxy-2-(naphthalen-2-yl)propane-thioate 3l
Colorless solid, yield: 82%; mp: 73.18C, IR nmax (KBr) cmꢀ1: 3372
O-Methyl 2-(3,4-dichlorophenyl)-2-hydroxypropane-thioate
3f
1
–
(OH), 1273 (C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.94 (s, 3H),
Pale yellow oil, yield: 85%; IR nmax (KBr) cmꢀ1: 3383 (OH), 1276
–
3
4.13 (s, 3H), 4.86 (s, 1H), 7.37–8.04 (m, 7H); 13C-NMR (400 MHz,
CDCl3), d (ppm): 27.2, 61.2, 80.5, 123.8, 124.6, 126.1, 126.2,
127.5, 127.9, 128.3, 132.7, 133.0, 141.1, 227.9; HRFAB-
MS C14H14O2S [MþH]þ: Calcd. 247.0793; found 247.0782.
1
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.80 (s, 3H), 4.15 (s, 3H),
–
–
3
4.77 (s, 1H), 7.37–7.67 (m, 3H); 13C-NMR (400 MHz, CDCl3),
d
(ppm): 27.4, 61.4, 79.6, 125.39, 128.0, 130.1, 131.8,
132.3, 143.9, 226.4; HRFAB-MS C10H10Cl2O2S [MþH]þ: Calcd.
264.9857; found 264.9845.
O-Propyl 2-hydroxy-2-(naphthalen-2-yl)propane-thioate 3m
Pale yellow oil, yield: 83%; IR nmax (KBr) cmꢀ1: 3384 (OH), 1282
O-Propyl 2-(3,4-dichlorophenyl)-2-hydroxypropane-thioate
3g
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 0.92 (t, J ¼ 7.1 Hz, 3H),
–
3
1.73–1.83 (q, 2H), 1.94 (s, 3H), 4.33–4.54 (m, 2H), 4.95 (s, 1H), 7.37–
8.06 (m, 7H); 13C-NMR (400 MHz, CDCl3), d (ppm): 10.4, 21.4, 27.3,
76.5, 80.4, 123.9, 124.6, 126.1, 126.1, 127.4, 127.8, 128.4, 132.7,
133.0, 141.2, 227.0; HRFAB-MS C16H18O2S [MþH]þ: Calcd.
275.1106; found 275.1094.
Pale yellow oil, yield: 84%; IR nmax (KBr) cmꢀ1: 3373 (OH), 1284
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 0.95 (t, J ¼ 7.0 Hz, 3H),
–
3
1.75–1.82 (m, 2H), 1.79 (s, 3H), 4.36–4.53 (m, 2H), 4.86 (s, 1H),
7.37–7.68 (m, 3H); 13C-NMR (400 MHz, CDCl3), d (ppm): 10.8, 21.8,
27.3, 77.2, 79.9, 125.7, 128.5, 130.4, 132.2, 132.6, 144.5, 225.9;
HRFAB-MS C12H14Cl2O2S [MþH]þ: Calcd. 293.0170; found
293.0159.
O-Benzyl 2-hydroxy-2-(naphthalen-2-yl)propane-thioate
3n
Pale yellow oil, yield: 80%, IR nmax (KBr) cmꢀ1: 3388 (OH), 1275
O-Benzyl 2-(3,4-dichlorophenyl)-2-hydroxypropane-
thioate 3h
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.75 (s, 3H), 4.87 (s, 1H),
–
3
5.42–5.54 (dd, 2H), 7.19–8.04 (m, 12H); 13C-NMR (400 MHz,
CDCl3), d (ppm): 27.6, 76.5, 81.1, 124.2, 125.1, 126.5, 126.6,
127.9, 128.2, 128.5, 128.8, 129.1, 129.1, 133.2, 133.4, 134.5,
141.5, 227.4; HRFAB-MS C20H18O2S [MþH]þ: Calcd. 323.1106;
found 323.1113.
Pale yellow oil, yield: 79%; IR nmax (KBr) cmꢀ1: 3382 (OH), 1278
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.79 (s, 3H), 4.78 (s, 1H),
–
3
5.44–5.54 (q, 2H), 7.22–7.66 (m, 8H); 13C-NMR (400 MHz,
CDCl3), d (ppm): 27.8, 76.9, 80.2, 125.7, 128.6, 128.7, 129.2,
129.4, 130.4, 132.3, 132.7, 134.2, 142.5, 225.4; HRFAB-
MS C16H14Cl2O2S [MþH]þ: Calcd. 341.0170; found 341.0178.
O-(2-Phenylethyl) 2-hydroxy-2-(naphthalen-2-yl)-
propanethioate 3o
O-(2-Phenylethyl) 2-(3,4-dichlorophenyl)-2-hydroxy-
propanethioate 3i
Colorless solid, yield: 83%, mp: 65.58C, IR nmax (KBr) cmꢀ1: 3386
1
(OH), 1263 (C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.85 (s, 3H),
–
–
3
Pale yellow oil, yield: 81%; IR nmax (KBr) cmꢀ1: 3378 (OH), 1285
3.04–3.05 (m, 2H), 4.60–4.77 (m, 2H), 4.84 (s, 1H), 7.06–7.96
(m, 12H); 13C-NMR (400 MHz, CDCl3), d (ppm): 27.6, 34.8, 75.3,
80.9, 124.2, 125.0, 126.5, 126.5, 127.2, 127.8, 128.2, 128.8,
128.0, 129.2, 133.1, 133.4, 137.4, 141.4, 223.8; HRFAB-
MS C21H20O2S [MþH]þ: Calcd. 337.1262; found 337.1248.
(C S); 1H-NMR (400 MHz, CDCl3), d (ppm): 1.69 (s, 3H), 3.06
–
–
(t, J ¼ 6.5 Hz, 2H), 4.63–4.77 (m, 2H), 4.74 (s, 1H), 7.11–7.58
(m, 8H); 13C-NMR (400 MHz, CDCl3), d (ppm): 27.4, 34.3, 75.1,
79.5, 125.2, 126.9, 128.0, 128.7, 128.8, 130.0, 131.7, 132.2, 136.8,
143.8, 225.4; HRFAB-MS C17H16Cl2O2S [MþH]þ: Calcd. 355.0326;
found 355.0321.
O-Benzyl 2-hydroxy-2-methylpropanethioate 3p
Pale yellow oil, yield: 88%, IR nmax (KBr) cmꢀ1: 3405 (OH), 1270
1
O-Ethyl 2-(3-bromo-4-fluorophenyl)-2-hydroxy-
propanethioate 3j
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.47 (s, 6H), 3.96 (s, 1H),
–
3
5.55 (s, 2H), 7.32–7.43 (m, 5H); 13C-NMR (400 MHz, CDCl3),
d (ppm): 29.1, 46.1, 76.0, 128.6, 129.0, 129.1, 134.9, 229.8;
HRFAB-MS C11H14O2S [MþH]þ: Calcd. 211.0714; found
211.0715.
Pale yellow oil, yield: 84%; IR nmax (KBr) cmꢀ1: 3375 (OH), 1285
1
–
(C S); H-NMR (400 MHz, CDCl ), d (ppm): 1.38 (t, J ¼ 7.1 Hz, 3H),
–
1.79 (s, 3H), 4.46–4.62 (m, 2H), 4.84 (s, 1H), 7.03–7.81 (m, 3H);
3
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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760
M. Khankischpur et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
1.29 (t, J ¼ 7.1 Hz, 3H), 1.72 (s, 3H), 4.07–4.17 (m, 4H), 7.29 (s, 1H),
7.47–7.53, 7.86–7.97 (m, 7H), 10.05 (s, 1H). Z-isomer: 0.93
(t, J ¼ 7.1 Hz, 3H), 1.24 (t, J ¼ 7.1 Hz, 3H), 1.68 (s, 3H), 3.57–
3.65, 4.19–4.27 (m, 4H), 6.33 (s, 1H), 7.47–7.53, 7.86–7.97
(m, 7H), 9.41 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
E-isomer: 14.0, 14.6, 28.6, 60.1, 62.1, 75.1, 122.5, 123.0, 125.8,
126.1, 127.4, 127.9, 128.1, 132.2, 132.5, 141.3. Z-isomer: 14.4, 14.9,
32.0, 60.2, 65.4, 77.2, 122.5, 123.0, 126.1, 126.3, 127.3, 127.8,
128.0, 132.0, 132.7, 143.0; anal. calcd. for C18H22N2O4: Calcd.
C 65.44%, H 6.71%, N 8.48%; found C 65.60%, H 6.72%, N 8.30%.
General procedure for the synthesis of compounds 4a–t, 7
To a stirring solution of 5 mmol of a-hydroxy thiocarboxylic
O-ester (3) in ethyl acetate (15 mL), 1.1 equivalents of the appro-
priate carbazate were added. The reaction mixture was stirred at
room temperature and monitored by thin-layer chromatography
(TLC). After completion, the reaction mixture was washed with
water (3 ꢁ 10 mL), the organic layer was separated, dried with
MgSO4 and evaporated under reduced pressure. The remaining
residue was crystallized from Et2O/n-hexane at 58C, delivering 4a,
c, h–t as solid compounds. Recrystallization from EtOAc/n-hex-
ane provided analytically pure products. Compounds 4b, e–g and
7 were prepared as follows: The appropriate carbazate (5.5 mmol)
was added dropwise to a solution of the imidate hydrochloride
salt (5 mmol) in anhydrous ethanol (10 mL) and the reaction
mixture was stirred at room temperature for 24 hours.
Afterwards, the solvent was evaporated and the remaining res-
idue was quenched with water (15 mL). The mixture was
extracted with ethyl acetate (2 ꢁ 30 mL), and the combined
organic layers were dried with MgSO4, filtered and concentrated
in vacuo. The remaining residues were purified by column
chromatography using EtOAc/n-hexane (1:1) as an eluent.
Crystallisation from Et2O/n-hexane at 58C afforded 4b, e–g as
solid compounds. Recrystallization from EtOAc/n-hexane pro-
vided analytically pure products.
tert-Butyl (2E/Z)-2-[1-ethoxy-2-hydroxy-2-(naphthalen-2-yl)-
propylidene]hydrazinecarboxylate 4d
Colorless solid, yield: 72%; mp: 160.28C; IR nmax (KBr) cmꢀ1: 3383
1
–
–
(NH), 3294 (OH), 1713 (C O), 1643 (C N); ratio E/Z ¼ 37:63; H-NMR
–
–
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.27 (t, J ¼ 7.1 Hz, 3H), 1.30
(s, 9H), 1.71 (s, 3H), 4.00–4.11 (m, 2H), 7.20 (s, 1H), 7.47–7.55, 7.88–
7.97 (m, 7H), 9.90 (s, 1H). Z-isomer: 0.92 (t, J ¼ 7.1 Hz, 3H), 1.47
(s, 9H), 1.71 (s, 3H), 3.56–3.63, 4.17–4.25 (m, 2H), 6.30 (s, 1H), 7.47–
7.55, 7.88–7.97 (m, 7H), 9.00 (s, 1H); 13C-NMR (400 MHz, DMSO-d6),
d (ppm): E-isomer: 14.5, 28.3, 29.0, 62.3, 77.5, 79.3, 123.0, 123.4,
126.5, 126.7, 127.8, 128.4, 128.5, 132.6, 132.9, 141.8. Z-isomer: 15.4,
28.5, 32.4, 65.8, 75.6, 79.4, 123.0, 123.4, 126.2, 126.8, 127.8, 128.2,
128.3, 132.4, 133.2, 143.4; anal. calcd. for C20H26N2O4: Calcd.
C 67.02%, H 7.31%, N 7.82%; found C 67.12%, H 7.63%, N 7.79%.
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-1-ethoxy-2-
hydroxypropylidene]hydrazinecarboxylate 4a
tert-Butyl (2E)-2-[1-ethoxy-2-hydroxy-2-(naphthalen-1-yl)-
ethylidene]hydrazinecarboxylate 4e
Colorless solid, yield: 76%; mp: 147.38C; IR nmax (KBr) cmꢀ1: 3392,
Colorless solid, yield: 34%; mp: 164.18C, IR nmax (KBr) cmꢀ1: 3359
–
–
3366 (NH), 3279 (OH), (C O), 1646 (C N); ratio E/Z ¼ 48:52;
–
–
1H-NMR (400 MHz, CDCl3), d (ppm): E-isomer: 1.23 (t, J ¼ 7.0 Hz,
3H), 1.35 (s, 9H), 1.62 (s, 3H), 4.00–4.06 (m, 2H), 7.33 (s, 1H), 7.15–
7.26 (m, 3H), 9.75 (s, 1H). Z-isomer: 1.01 (t, J ¼ 7.0 Hz, 3H), 1.44
(s, 9H), 1.57 (s, 3H), 3.59–3.67, 4.11–4.19 (m, 2H), 6.40 (s, 1H), 7.15–
7.26 (m, 3H), 9.10 (s, 1H); 13C-NMR (400 MHz, CDCl3), d (ppm):
E-isomer: 14.4, 28.5, 28.6, 62.5, 77.0, 79.4, 125.6, 126.8, 131.0,
129.9, 131.4, 145,3. Z-isomer: 15.5, 28.6, 31.8, 66.0, 75.0, 79.4,
125.4, 126.9, 131.1, 129.9, 131.4, 143.7; anal. calcd.
for C16H22Cl2N2O4: Calcd. C 50.94%, H 5.88%, N 7.43%; found C
50.76%, H 5.93%, N 7.33%.
(NH), 3292 (OH), 1707 (C O), 1654 (C N); 1H-NMR (400 MHz,
–
–
–
–
DMSO-d6), d (ppm): 1.07 (t, J ¼ 7.1 Hz, 3H), 1.41 (s, 9H), 3.93–
4.05 (m, 2H), 6.28 (d, 1H), 6.83 (d, 1H), 7.49–7.56, 7.89–7.91, 7.94–
8.08 (m, 7H), 9.85 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
14.3, 28.5, 62.1, 69.4, 79.3, 124.2, 124.7, 125.7, 126.2, 126.5, 128.9,
128.9, 130.9, 133.8, 135.0, 152.8, 156.6; anal. calcd.
for C19H24N2O4: Calcd. C 66.26%, H 7.02%, N 8.13%; found
C 66.59%, H 7.06%, N 8.04%.
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-1-ethoxy-2-
hydroxyethylidene]hydrazinecarboxylate 4f
Methyl (2E/Z)-2-[2-(4-chloro-3-methylphenyl)-1-ethoxy-2-
hydroxypropylidene]hydrazinecarboxylate 4b
Colorless solid, yield: 37%; mp: 108.98C; IR nmax (KBr) cmꢀ1: 3387
1
–
–
(NH), 3310 (OH), 1711 (C O), 1655 (C N); ratio E/Z ¼ 60:40; H-NMR
–
–
Colorless solid, yield: 37%; mp: 137.48C; IR nmax (KBr) cmꢀ1: 3372
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.15 (t, J ¼ 7.1 Hz, 3H), 1.41
(s, 9H), 3.94–4.01 (m, 2H), 5.63 (d, 1H), 6.76 (d, 1H), 7.58–7.65
(m, 3H), 9,63 (s, 1H). Z-isomer: 1.15 (t, J ¼ 7.1 Hz, 3H), 1.41
(s, 9H), 4.19–4.26 (m, 2H), 5.62 (d, 1H), 6.56 (d, 1H), 7.32–7.35
(m, 3H), 9.01 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
E-isomer: 15.4, 28.4, 62.3, 68.5, 75.4, 126.9, 128.5, 130.6, 130.5,
131.2, 142.2. Z-isomer: 14.3, 28.4, 64.9, 70.24, 79.4, 127.3, 128.3,
130.7, 130.1, 131.1, 141.3; anal. calcd. for C15H20Cl2N2O4: Calcd.
C 49.60%, H 5.55%, N 7.71%; found C 49.28%, H 5.66%, N 7.64%.
1
–
–
(NH), 3319 (OH), 1720 (C O), 1642 (C N); ratio E/Z ¼ 68:32; H-NMR
–
–
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.25 (t, J ¼ 7.1 Hz, 3H), 1.59
(s, 3H), 2.33 (s, 3H), 3.54 (s, 3H), 4.01–4.06 (m, 2H), 7.22 (s, 1H), 7.32–
7.42 (m, 3H), 9.95 (s, 1H). Z-isomer: 0.99 (t, J ¼ 7.1 Hz, 3H), 1.55
(s, 3H), 2.34 (s, 3H), 3.65 (s, 3H), 3.59–3.63, 4.13–4.21 (m, 2H), 6.22
(s, 1H), 7.19–7.26 (m, 3H), 9.44 (s, 1H); 13C-NMR (400 MHz, DMSO-d6),
d (ppm): E-isomer: 14.4, 20.2, 29.1, 52.1, 62.5, 77.1, 123.8, 127.6,
129.2, 132.7, 133.5, 135.7, 143.3, 144.9. Z-isomer: 15.4, 19.5, 32.3,
52.1, 65.9, 75.0, 124.1, 127.4, 129.0, 132.1, 135.0, 135.5, 143.3,
144.9; anal. calcd. for C14H19ClN2O4: Calcd. C 53.42%, H 6.08%,
N 8.90%; found C 53.29%, H 6.25%, N 8.81%.
Ethyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-1-ethoxy-2-
hydroxybutylidene]hydrazinecarboxylate 4g
Colorless solid, yield: 37%; mp: 107.88C; IR nmax (KBr) cmꢀ1: 3364
Ethyl (2E/Z)-2-[1-ethoxy-2-hydroxy-2-(naphthalen-2-yl)-
propylidene]hydrazinecarboxylate 4c
–
–
(NH), 3310 (OH), 1723 (C O), 1648 (C N); ratio E/Z ¼ 93:7;
–
–
(ppm): E-isomer: 0.82
1H-NMR (400 MHz, DMSO-d6),
d
Colorless solid, yield: 74%; mp: 122.78C; IR nmax (KBr) cmꢀ1: 3372
(t, J ¼ 7.1 Hz, 3H), 1.15 (t, J ¼ 7.1 Hz, 3H), 1.23 (t, J ¼ 7.1 Hz,
3H), 1.79–1.88, 2.13–2.22 (m, 2H), 3.96–4.06 (m, 4H), 7.12
(s, 1H), 7.38–7.41, 7.61–7.66 (m, 3H), 10.16 (s, 1H). Z-isomer:
(NH, OH), 1717 (C O), 1637 (C N); ratio E/Z ¼ 50:50; 1H-NMR
–
–
–
–
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.09 (t, J ¼ 7.1 Hz, 3H),
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Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Facile Synthesis and In-Vitro Antimalarial Activity . . .
761
0.63 (t, J ¼ 7.1 Hz, 3H), 1.01 (t, J ¼ 7.1 Hz, 3H), 1.10 (t, J ¼ 7.1 Hz,
3H), 1.90–1.95, 2.04–2.11 (m, 2H), 3.59–3.67, 4.08–4.19 (m, 4H), 6.08
(s, 1H), 7.29–7.31, 7.50–7.59 (m, 3H), 9.50 (s, 1H);13C-NMR (400 MHz,
DMSO-d6), d (ppm): E-isomer: 8.0, 14.3, 14.9, 32.7, 60.6, 62.5, 80.4,
125.8, 127.3, 130.9, 130.6, 131.3, 144.4, 152.2, 154.0. Z-isomer: 7.8,
15.0, 15.3, 34.6, 60.6, 65.8, 77.1, 126.1, 127.6, 130.7, 129.9, 131.2,
144.9, 152.2, 154.0; anal. calcd. for C15H20Cl2N2O4: Calcd. C 49.60%,
H 5.55%, N 7.71%; found C 49.51%, H 5.72%, N 7.63%.
DMSO-d6), d (ppm): 1.15 (t, J ¼ 7.1 Hz, 3H), 1.64 (s, 3H), 3.98–
4.10 (m, 2H), 5.00–5.08 (m, 2H), 7.32 (s, 1H), 7.42–7.46 (m, 8H),
9.99 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm): 14.4, 28.3,
60.3, 67.0, 77.0, 126.3, 126.4, 127.5, 127.9, 128.2, 128.3, 129.2,
129.8, 132.1, 132.4, 135.5, 142.6, 144.1; anal. calcd.
for C19H20Cl2N2O4: Calcd. C 55.49%, H 4.90%, N 6.81%; found
C 55.32%, H 5.06%, N 6.60%.
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-2-hydroxy-1-
methoxypropylidene]hydrazinecarboxylate 4l
Benzyl (2E/Z)-2-[1-ethoxy-2-hydroxy-2-(4-methyl-
phenyl)propylidene]hydrazinecarboxylate 4h
Colorless solid, yield: 76%; mp: 155.38C; IR nmax (KBr) cmꢀ1: 3360
Colorless solid, yield: 82%; mp: 101.78C; IR nmax (KBr) cmꢀ1: 3445
(NH), 3317 (OH), 1710 (C O), 1643 (C N); ratio E/Z ¼ 94:6;
–
–
–
–
–
–
(NH), 3324 (OH), 1718, 1683 (C O), 1653, 1637 (C N); ratio
1H-NMR (400 MHz, CDCl3), d (ppm): E-isomer: 1.36 (s, 9H), 1.63
(s, 3H), 3.63 (s, 3H), 7.35 (s, 1H), 7.33–7.64 (m, 3H), 9.77 (s, 1H).
Z-isomer: 1.44 (s, 9H), 1.57 (s, 3H), 3.54 (s, 3H), 6.40 (s, 1H), 7.33–
7.64 (m, 3H), 9.24 (s, 1H); 13C-NMR (400 MHz, CDCl3), d (ppm):
E-isomer: 28.3, 28.5, 54.4, 77.1, 79.5, 125.5, 127.0, 131.0, 130.6,
131.4, 145.4; Z-isomer: 28.4, 31.7, 58.0, 74.9, 79.4, 125.5, 126.9,
131.0, 130.0, 131.4, 147.0; anal. calcd. for C15H20Cl2N2O4: Calcd.
C 49.60%, H 5.55%, N 7.71%; found C 49.38%, H 5.69%, N 7.60%.
–
–
E/Z ¼ 70:30; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
1.27 (t, J ¼ 7.1 Hz, 3H), 1.80 (s, 3H), 2.33 (s, 3H), 4.06–4.16
(m, 2H), 5.09 (s, 2H), 7.10 (s, 1H), 7.25–7.42 (m, 9H), 9.76
(s, 1H). Z-isomer: 1.01 (t, J ¼ 7.1 Hz, 3H), 1.74 (s, 3H), 2.33
(s, 3H), 3.58–3.66, 4.13–4.20 (m, 2H), 5.22 (s, 2H), 6.06 (s, 1H),
7.25–7.42 (m, 9H), 8.23 (s, 1H); 13C-NMR (400 MHz, DMSO-d6),
d (ppm): E-isomer: 14.2, 21.1, 29.2, 66.6, 66.7, 78.5, 124.5,
128.4, 128.6, 129.2, 137.7, 140.5. Z-isomer: 15.3, 21.1, 31.0,
62.8, 67.3, 76.7, 124.8, 128.0, 128.4, 128.4, 129.2, 137.2, 140.2;
anal. calcd. for C20H24N2O4: Calcd. C 67.40%, H 6.79%, N 7.86%;
found C 67.36%, H 6.80%, N 7.88%.
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-2-hydroxy-1-
propoxypropylidene]hydrazinecarboxylate 4m
Colorless solid, yield: 67%; mp: 55.98C; IR nmax (KBr) cmꢀ1: 3354
(NH), 3314 (OH), 1708 (C O), 1647 (C N); 1H-NMR (400 MHz,
–
–
–
–
Methyl (2E/Z)-2-[2-(3,4-dimethylphenyl)-1-ethoxy-2-
hydroxypropylidene]hydrazinecarboxylate 4i
DMSO-d6), d (ppm): E-isomer: 0.90 (t, J ¼ 7.1 Hz, 3H), 1.36
(s, 9H), 1.63 (s, 3H), 1.61–1.66 (m, 2H), 3.86–3.96 (m, 2H), 7.34
(s, 1H), 7.30–7.70 (m, 3H), 9.77 (s, 1H). Z-isomer: 0.66 (t, J ¼ 7.1 Hz,
3H), 1.44 (s, 9H), 1.57 (s, 3H), 1.34–1.39 (m, 2H), 3.53–4.07 (m, 2H),
6.39 (s, 1H), 7.30–7.70 (m, 3H), 9.02 (s, 1H); 13C-NMR (400 MHz,
DMSO-d6), d (ppm): E-isomer: 10.8, 21.8, 28.3, 28.5, 68.2, 77.1, 79.4,
125.4, 127.0, 131.0, 130.5, 131.4, 145.5; Z-isomer: 10.3, 22.7, 28.4,
31.8, 71.5, 75.0, 79.5, 125.5, 126.9, 130.9, 130.5, 131.4, 147.1; anal.
calcd. for C17H24Cl2N2O4: Calcd. C 52.18%, H 6.18%, N 7.16%;
found C 52.25%, H 6.49%, N 7.03%.
Colorless solid, yield: 83%; mp: 142.38C; IR nmax (KBr) cmꢀ1: 3394
–
–
(NH), 3343 (OH), 1716, 1686 (C O), 1637 (C N); ratio E/Z ¼ 37:63;
–
–
(ppm): E-isomer: 1.26
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.1 Hz, 3H), 1.56 (s, 3H), 2.19 (s, 3H), 2.21 (s, 3H), 3.53
(s, 3H), 3.99–4.06 (m, 2H), 7.04 (s, 1H), 7.06–7.15 (m, 3H), 10.00
(s, 1H). Z-isomer: 0.97 (t, J ¼ 7.1 Hz, 3H), 1.52 (s, 3H), 2.19 (s, 3H),
2.20 (s, 3H), 3.65 (s, 3H), 3.56–4.22 (m, 2H), 6.05 (s, 1H), 7.06–7.15
(m, 3H), 9.38 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
E-isomer: 14.2, 19.4, 20.1, 29,4, 52.1, 62.4, 77.2, 122.0, 125.6,
129.7, 135.0, 136.2, 143.2, 171.6, 174.9. Z-isomer: 114.5, 19.4,
20.1, 32.6, 52.1, 65.7, 72.8, 121.9, 125.6, 129.7, 135.7, 136.4,
141.7, 171.6, 174.9; anal. calcd. for C15H22N2O4: Calcd. C
61.21%, H 7.53%, N 9.52%; found C 60.91%, H 7.50%, N 9.32%.
tert-Butyl (2E/Z)-2-[1-(benzyloxy)-2-(3,4-dichloro-phenyl)-
2-hydroxypropylidene]hydrazinecarboxylate 4n
Colorless solid, yield: 81%; mp: 131.88C; IR nꢀm1ax (KBr) cmꢀ1
:
3380 cmꢀ1 (NH), 1701 cmꢀ1 (C O), 1637 cm
–
–
–
(C N); ratio
–
E/Z ¼ 75:25; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
1.38 (s, 9H), 1.66 (s, 3H), 5.05 (s, 2H), 7.40 (s, 1H), 7.12–7.64
(m, 8H), 9.81 (s, 1H). Z-isomer: 1.43 (s, 9H), 1.61 (s, 3H), 4.80–
5.15 (dd, 2H), 6.56 (s, 1H), 7.12–7.64 (m, 8H), 9.11 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6), d (ppm): E-isomer: 27.9, 28.0, 67.7, 76.7,
79.1, 125.0, 126.6, 127.3, 127.8, 127.9, 128.2, 130.6, 130.2,
130.9, 136.50, 144.82. Z-isomer: 28.0, 31.4, 70.8, 74.7, 79.2,
124.6, 126.5, 127.3, 127.7, 127.9, 128.2, 130.5, 129.5, 130.1,
136.7, 143.4; anal. calcd. for C21H24Cl2N2O4: Calcd. C 57.41%,
H 5.51%, N 6.38%; found C 57.21%, H 5.63%, N 6.26%.
Ethyl (2E/Z)-2-[2-(4-chlorophenyl)-1-ethoxy-2-
hydroxypropylidene]hydrazinecarboxylate 4j
Colorless solid, yield: 76%; mp: 108.98C; IR nmax (KBr) cmꢀ1: 3323
–
–
(NH), 3336 (OH), 1734, 1718 (C O), 1654, 1638 (C N); ratio
–
–
E/Z ¼ 50:50; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
1.13 (t, J ¼ 7.1 Hz, 3H), 1.24 (t, J ¼ 7.1 Hz, 3H), 1.60 (s, 3H),
3.93–4.07 (m, 4H), 7.23 (s, 1H), 7.18–7.45 (m, 4H), 9.87 (s, 1H).
Z-isomer: 0.98 (t, J ¼ 7.1 Hz, 3H), 1.22 (t, J ¼ 7.1 Hz, 3H), 1.56
(s, 3H), 3.57–4.17 (m, 4H), 6.24 (s, 1H), 7.18–7.45 (m, 4H), 8.36
(s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 13.9,
14.5, 28.6, 60.1, 62.1, 76.9, 126.2, 128.3, 132.2, 142.9. Z-isomer:
14.6, 16.0, 31.8, 60.2, 65.4, 74.8, 126.3, 128.2, 131.4, 144.5; anal.
calcd. for C14H19ClN2O4: Calcd. C 53.42%, H 6.08%, N 8.90%;
found C 53.31%, H 6.20%, N 8.83%.
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-2-hydroxy-1-
(2-phenylethoxy)propylidene]hydrazinecarboxylate 4o
Colorless solid, yield: 75%; mp: 147.98C; IR nmax (KBr) cmꢀ1: 3393
–
–
–
(NH), 3336 (OH), 1704 (C O), 1654 (C N); ratio E/Z ¼ 57:43;
–
1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 1.35 (s, 9H),
1.55 (s, 3H), 2.90–2.97 (m, 2H), 4.09–4.19 (m, 2H), 7.32 (s, 1H),
7.02–7.60 (m, 8H), 9.76 (s, 1H). Z-isomer: 1.44 (s, 9H), 1.55 (s, 3H),
2.65–2.80 (m, 2H), 3.84–4.29 (m, 2H), 6.45 (s, 1H), 7.02–7.60
(m, 8H), 8.76 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
Ethyl (2E)-2-{1-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)-
2-hydroxypropylidene}hydrazinecarboxylate 4k
Colorless solid, yield: 75%; mp: 151.78C; IR nmax (KBr) cmꢀ1: 3348
(NH), 3326 (OH), 1709 (C O), 1638 (C N); 1H-NMR (400 MHz,
–
–
–
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

762
M. Khankischpur et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
E-isomer: 27.9, 28.0, 34.2, 70.1, 76.5, 79.1, 124.9, 126.1, 126.4,
128.2, 128.8, 130.4, 130.1, 130.9, 138.6, 144.8. Z-isomer: 27.9, 31.2,
35.1, 67.2, 74.5, 79.0, 125.0, 126.1, 126.4, 128.2, 128.5, 130.5,
123.0, 131.0, 137.8, 146.4; anal. calcd. for C22H26Cl2N2O4: Calcd. C
58.28%, H 5.78%, N 6.18%; found C 58.16%, H 5.91%, N 6.09%.
(400 MHz, DMSO-d6), d (ppm): E-isomer: 14.8, 29.0, 60.7, 68.2, 77.8,
123.1, 123.4, 126.6, 126.7, 127.8, 128.2, 128.3, 128.5, 128.7, 132.6,
132.9, 137.1, 141.6. Z-isomer: 15.0, 32.4, 60.7, 71.2, 75.7, 123.2,
123.4, 126.3, 126.7, 127.8, 128.0, 128.1, 128.4, 128.5, 132.5, 133.2,
137.1, 143.3; anal. calcd. for C23H24N2O4: Calcd. C 70.39%,
H 6.16%, N 7.14%; found C 70.19%, H 6.24%, N 6.94%.
Ethyl (2E/Z)-2-[2-(3-bromo-4-fluorophenyl)-1-ethoxy-2-
hydroxypropylidene]hydrazinecarboxylate 4p
Ethyl (2E/Z)-2-[2-hydroxy-2-(naphthalen-2-yl)-1-
(2-phenylethoxy)propylidene]hydrazinecarboxylate 4t
Colorless solid, yield: 82%; mp: 102.38C; IR nmax (KBr) cmꢀ1: 3358
1
(NH), 3334 (OH), 1720 (C O), 1637 (C N); H-NMR (400 MHz, DMSO-
Colorless solid, yield: 77%; mp: 150.18C; IR nmax (KBr) cmꢀ1: 3373
–
–
–
–
–
–
d6), d (ppm): E-isomer: 1.13 (t, J ¼ 7.1 Hz, 3H), 1.24 (t, J ¼ 7.1 Hz, 3H),
1.62 (s, 3H), 3.95–4.06 (m, 4H), 7.37 (s, 1H), 7.39–7.69 (m, 3H), 9.94
(s, 1H). Z-isomer: 1.01 (t, J ¼ 7.1 Hz, 3H), 1.22 (t, J ¼ 7.1 Hz, 3H), 1.57
(s, 3H), 3.61–4.16 (m, 4H), 6.36 (s, 1H), 7.42–7.44 (m, 3H), 9.47 (s, 1H);
13C-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 14.4, 14.9, 28.9, 60.6,
62.6, 77.1, 107.8 (d, 2JC,F ¼ 21.4 Hz), 117.0 (d, 2JC,F ¼ 22.1 Hz), 126.3
(NH), 3326 (OH), 1710 (C O), 1654 (C N); ratio E/Z ¼ 90:10;
–
–
(ppm): E-isomer: 1.09
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.1 Hz, 3H), 1.65 (s, 3H), 2.98 (t, J ¼ 5.9 Hz, 2H), 3.90–
4.04 (m, 2H), 4.18–4.24 (m, 2H), 7.29 (s, 1H), 7.23–7.89
(m, 12H), 10.04 (s, 1H). Z-isomer: 1.24 (t, J ¼ 7.1 Hz, 3H), 1.67
(s, 3H), 2.53–2.76 (m, 2H), 4.10–4.16 (m, 2H), 4.27–4.37 (m, 2H),
6.39 (s, 1H), 6.84–7.89 (m, 12H), 9.17 (s, 1H); 13C-NMR (400 MHz,
DMSO-d6), d (ppm): E-isomer: 14.4, 28.5, 34.3, 60.1, 67.3, 77.2,
122.4, 122.8, 126.1, 126.2, 126.2, 127.3, 127.9, 128.0, 128.2, 128.9,
132.1, 132.4, 138.8, 141.1. Z-isomer: 14.5, 31.8, 35.1, 60.2, 69.8,
75.1, 122.7, 123.0, 125.8, 126.0, 126.2, 127.4, 127.9, 128.1, 128.4,
128.9, 132.0, 132.7, 137.7, 142.7; anal. calcd. for C24H26N2O4:
Calcd. C 70.92%, H 6.45%, N 6.89%; found C 70.67%, H 6.60%,
N 6.63%.
3
3
4
(d, JC,F ¼ 7.6 Hz), 128.6 (d, JC,F ¼ 7.6 Hz), 142.2 (d, JC,F ¼ 3.1 Hz),
157.8 (d, 1JC,F ¼ 244.9 Hz). Z-isomer: 14.9, 15.4, 32.2, 60.6, 66.0, 75.0,
2
2
107.8 (d, JC,F ¼ 21.4 Hz), 117.0 (d, JC,F ¼ 22.1 Hz), 126.3
3
3
4
(d, JC,F ¼ 7.6 Hz), 128.6 (d, JC,F ¼ 7.6 Hz), 142.2 (d, JC,F ¼ 3.1 Hz),
1
157.8 (d, JC,F ¼ 244.9 Hz); anal. calcd. for C14H18BrFN2O4: Calcd. C
44.58%, H 4.81%, N 7.43%; found C 44.40%, H 4.95%, N 7.45%.
Ethyl (2E)-2-[2-hydroxy-1-methoxy-2-(naphthalen-2-yl)-
propylidene]hydrazinecarboxylate 4q
Colorless solid, yield: 80%; mp: 138.38C; IR nmax (KBr) cmꢀ1: 3349
tert-Butyl (2E/Z)-2-[2-(3,4-dichlorophenyl)-1-ethoxy-
ethylidene]hydrazinecarboxylate 7
(NH), 1718 (C O), 1641 (C N); 1H-NMR (400 MHz, DMSO-d6),
–
–
–
–
d (ppm): 1.10 (t, J ¼ 7.1 Hz, 3H), 1.72 (s, 3H), 3.69 (s, 3H), 3.93–
4.04 (m, 2H), 7.31 (s, 1H), 7.50–7.98 (m, 7H), 10.07 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6), d (ppm): 14.8, 29.0, 54.9, 60.6, 77.8, 123.0,
123.4, 126.6, 126.8, 127.8, 128.5, 128.5, 132.6, 132.9, 141.7; anal.
calcd. for C17H20N2O4: Calcd. C 64.54%, H 6.37%, N 8.86%; found C
64.42%, H 6.45%, N 8.70%.
Colorless solid, yield: 84%; mp: 128.18C; IR nmax (KBr) cmꢀ1: 3221,
1
–
–
3192 (NH), 1717, 1694 (C O), 1655 (C N); ratio E/Z ¼ 56:44; H-
–
–
NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 1.16 (t, J ¼ 7.1 Hz,
3H), 1.42 (s, 9H), 3.73 (s, 2H), 3.96–4.05 (m, 2H), 7.18–7.61 (m, 3H),
9.39 (s, 1H). Z-isomer: 1.18 (t, J ¼ 7.1 Hz, 3H), 1.41 (s, 9H), 3.76
(s, 2H), 3.96–4.05 (m, 2H), 7.18–7.61 (m, 3H), 8.95 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6), d (ppm): E-isomer: 15.6, 28.7, 36.1, 64.9,
81.3, 128.0, 130.5, 131.2, 131.7, 133.3, 136.0. Z-isomer: 14.5,
28.7, 34.5, 63.3, 81.1, 128.6, 130.5, 131.0, 131.5, 133.1, 135.0;
anal. calcd. for C15H20Cl2N2O: Calcd. C 51.88%, H 5.81%, N 8.07%;
found C 51.49%, H 5.88%, N 8.31%.
Ethyl (2E/Z)-2-[2-hydroxy-2-(naphthalen-2-yl)-1-
propoxypropylidene]hydrazinecarboxylate 4r
Colorless solid, yield: 81%; mp: 122.88C; IR nmax (KBr) cmꢀ1: 3369
–
–
(NH), 3326 (OH), 1718, 1686 (C O), 1637, 1622 (C N); ratio
–
–
E/Z ¼ 57:43; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
0.94 (t, J ¼ 7.1 Hz, 3H), 1.09 (t, J ¼ 7.1 Hz, 3H), 1.64–1.71
(m, 2H), 1.74 (s, 3H), 3.92–4.03 (m, 4H), 7.31 (s, 1H), 7.47–7.96
(m, 7H), 10.07 (s, 1H). Z-isomer: 0.56 (t, J ¼ 7.1 Hz, 3H), 1.24
(t, J ¼ 7.1 Hz, 3H), 1.29–1.41 (m, 2H), 1.67 (s, 3H), 3.51–4.18
(m, 4H), 6.33 (s, 1H), 7.47–7.96 (m, 7H), 9.32 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6), d (ppm): E-isomer: 10.5, 14.4, 21.4, 28.5,
60.2, 67.8, 77.4, 122.5, 122.9, 126.1, 126.3, 127.3, 127.9, 128.0,
132.2, 132.7, 141.3, 153.5. Z-isomer: 9.8, 14.6, 22.2, 32.0, 60.1,
71.0, 75.1, 122.6, 123.0, 125.8, 126.1, 127.4, 127.8, 128.0, 132.0,
132.5, 142.9, 152.4; anal. calcd. for C19H24N2O4: Calcd. C 66.26%,
H 7.02%, N 8.13%; found C 66.14%, H 6.98%, N 8.20%.
General procedure for the synthesis of compounds 5a–g,
6a
To a stirring solution of the appropriate a-hydroxy thio-
carboxylic O-ester 3 (5 mmol) in ethyl acetate (15 mL), the
appropriate (thio)semicarbazide [15] (6 mmol) was added.
The reaction mixture was stirred at room temperature and
monitored by thin-layer chromatography (TLC). After completion
of the reaction the organic layer was washed with water
(3 ꢁ 10 mL), dried with MgSO4 and evaporated. After removal
of the solvent the remaining residue was crystallized from Et2O/
n-hexane at 58C to afford 5a–g, 6a as solid compounds.
Recrystallization from EtOAc/n-hexane provided analytically
pure products.
Ethyl (2E/Z)-2-[1-(benzyloxy)-2-hydroxy-2-(naphthalen-
2-yl)propylidene]hydrazinecarboxylate 4s
Colorless solid, yield: 87%; mp: 133.98C; IR nmax (KBr) cmꢀ1: 3356
Ethyl (1E/Z)-2-hydroxy-N-(methylcarbamoyl)-2-
(naphthalen-2-yl)propanehydrazonoate 5a
–
–
(NH), 3326 (OH), 1715, 1709 (C O), 1655, 1637 (C N); ratio
–
–
E/Z ¼ 70:30; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
1.12 (t, J ¼ 7.1 Hz, 3H), 1.76 (s, 3H), 3.95–4.05 (m, 2H), 5.13
(s, 2H), 7.36 (s, 1H), 7.06–8.02 (m, 7H), 10.11 (s, 1H). Z-isomer:
1.23 (t, J ¼ 7.1 Hz, 3H), 1.72 (s, 3H), 4.10–4.15 (m, 2H), 4.70–5.24
(dd, 2H), 6.50 (s, 1H), 7.06–8.02 (m, 7H), 9.39 (s, 1H); 13C-NMR
Colorless solid, yield: 84%; mp: 173.68C; IR nmax (KBr) cmꢀ1: 3432,
–
–
3302, 3177 (NH, OH), 1654 (C O), 1644 (C N); ratio E/Z ¼ 62:38;
–
–
(ppm): E-isomer: 1.28
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.0 Hz, 3H), 1.69 (s, 3H), 2.58 (d, 3H), 4.09–4.14 (m, 2H),
6.70 (d, 1H), 7.08 (s, 1H), 7.48–7.97 (m, 7H), 9.13 (s, 1H). Z-isomer:
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Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
Facile Synthesis and In-Vitro Antimalarial Activity . . .
763
0.93 (t, J ¼ 7.0 Hz, 3H), 1.71 (s, 3H), 2.71 (d, 3H), 3.55–4.22 (m, 2H),
Ethyl (1E/Z)-N-(benzylcarbamoyl)-2-(3,4-dichlorophenyl)-
2-hydroxypropanehydrazonoate 5e
6.22 (s, 1H), 6,35 (d, 1H), 7.48–7.97 (m, 7H), 8.54 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6),
d (ppm): E-isomer: 14.5, 26.4, 29.2,
Colorless solid, yield: 83%; mp: 158.48C; IR nmax (KBr) cmꢀ1: 3424,
62.4, 77.2, 122.9, 123.4, 126.5, 126.7, 127.8, 128.4, 128.5,
132.6, 132.9, 141.9, 152.4, 156.1. Z-isomer: 15.4, 26.6, 31.9,
65.7, 75.4, 123.1, 123.7, 126.2 126.6, 127.8, 128.1, 128.3,
132.4, 133.1, 143.5, 156.1, 156.6; anal. calcd. for C17H21N3O3:
Calcd. C 64.74%, H 6.71%, N 13.32%; found C 64.89%, H 6.86%,
N 13.11%.
–
–
3408, 3301 (NH, OH), 1656 (C O), 1647 (C N); ratio E/Z ¼ 58:42;
–
–
(ppm): E-isomer: 1.24
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.0 Hz, 3H), 1.64 (s, 3H), 4.07–4.12 (m, 2H), 4.23–4.30
(m, 2H), 7.26 (s, 1H), 7.06–7.66 (m, 9H), 9.16 (s, 1H). Z-isomer:
1.03 (t, J ¼ 7.0 Hz, 3H), 1.62 (s, 3H), 3.62–4.21 (m, 2H), 4.30–4.41
(m, 2H), 6.33 (s, 1H), 7.06–7.66 (m, 9H), 8.79 (s, 1H); 13C-NMR
(400 MHz, DMSO-d6), d (ppm): E-isomer: 14.4, 28.8, 42.8, 62.6,
76.6, 125.4, 126.8, 131.0, 127.1, 127.2, 128.5, 130.5, 131.4,
141.1, 145.5, 149.7, 155.8. Z-isomer: 15.4, 31.3, 42.9, 66.0, 74.8,
125.6, 126.9, 130.9, 127.1, 127.3, 128.6, 129.9, 131.3, 141.1, 147.2,
149.6, 156.0; anal. calcd. for C19H21Cl2N3O3: Calcd. C 55.62%,
H 5.16%, N 10.24%; found C 55.88%, H 5.48%, N 10.51%.
Ethyl (1E/Z)-N-(benzylcarbamoyl)-2-hydroxy-2-
(naphthalen-2-yl)propanehydrazonoate 5b
Colorless solid, yield: 82%; mp: 158.88C; IR nmax (KBr) cmꢀ1: 3424,
–
–
3318, 3254 (NH, OH), 1649 (C O), 1632 (C N); ratio E/Z ¼ 60:40;
–
–
(ppm): E-isomer: 1.28
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.0 Hz, 3H),1.71 (s, 3H), 4.11–4.16 (m, 2H), 4.20–4.26
(m, 2H), 7.17 (s, 1H), 7.13–8.00 (m, 12H), 7.03 (t, J ¼ 6.6 Hz,
1H), 9.27 (s, 1H). Z-isomer: 0.94 (t, J ¼ 7.0 Hz, 3H), 1.73 (s, 3H),
3.57–4.45 (m, 4H), 6.25 (s, 1H), 7.13–8.00 (m, 13H), 8.72 (s, 1H);
13C-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 14.0, 28.7, 42.3,
62.0, 76,8, 122.7, 123.2, 125.9, 126.1, 126.5, 126.7, 126.9, 127.4,
127.7, 127.9, 128.0, 128.1, 132.0, 132.7, 140.7, 143.0, 150.0, 155.7.
Z-isomer: 15.0, 31.5, 42.5, 65.4, 75.0, 122.5, 122.9, 126.0,
126.2, 126.3, 126.8, 126.9, 127.3, 127.8, 127.9, 128.0, 128.1,
132.1, 132.5, 141.4, 143.0, 152.2, 155.3; anal. calcd.
for C23H25N3O3: Calcd. C 70.57%, H 6.44%, N 10.73%; found
C 70.51%, H 6.44%, N 10.39%.
Ethyl (1E/Z)-2-(3,4-dichlorophenyl)-2-hydroxy-N-
[(4-methylbenzyl)carbamoyl]propanehydrazonoate 5f
Colorless solid, yield: 79%; mp: 157.48C; IR nmax (KBr) cmꢀ1: 3487,
–
–
3354, 3246 (NH, OH), 1655 (C O), 1646 (C N); ratio E/Z ¼ 8:92;
–
–
(ppm): E-isomer: 1.24
1H-NMR (400 MHz, DMSO-d6),
d
(t, J ¼ 7.0 Hz, 3H),1.60 (s, 3H), 2.25 (s, 3H), 4.08–4.18 (m, 2H),
4.23–4.36 (m, 2H), 7.09 (s, 1H), 7.12–7.63 (m, 8H), 9.14 (s, 1H).
Z-isomer: 1.03 (t, J ¼ 7.0 Hz, 3H), 1.63 (s, 3H), 2.28 (s, 3H), 3.61–
4.18 (m, 2H), 4.23–4.36 (m, 2H), 6.32 (s, 1H), 7.01 (s, 1H), 7.12–7.63
(m, 7H), 8.77 (s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm):
E-isomer: 14.4, 21.0, 28.8, 42.7, 62.6, 76.6, 125.3, 126.8, 131.0,
127.2, 129.0, 130.5, 131.4, 135.8, 138.1, 145.5, 151.6, 155.7.
Z-isomer: 15.5, 21.0, 31.3, 42.5, 66.0, 74.8, 125.6, 127.1, 130.9,
127.4, 129.1, 129.9, 131.3, 135.9, 138.0, 147.2, 149.6, 156.0; anal.
calcd. for C20H23Cl2N3O3: Calcd. C 56.61%, H 5.46%, N 9.90%;
found C 56.25%, H 5.60%, N 9.82%.
Ethyl (1E/Z)-N-[(benzyloxy)carbamoyl]-2-hydroxy-2-
(naphthalen-2-yl)propanehydrazonoate 5c
Colorless solid, yield: 78%; mp: 129.68C; IR nmax (KBr) cmꢀ1: 3365,
1
–
–
3223 (NH, OH), 1678 (C O), 1647 (C N); ratio E/Z ¼ 5:95; H-NMR
–
–
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.31 (t, J ¼ 7.1 Hz, 3H),
1.72 (s, 3H), 4.07–4.13 (m, 2H), 4.81 (s, 2H), 7.26 (s, 1H), 7.33–7.95
(m, 12H), 9.39 (s, 1H), 10.40 (s, 1H). Z-isomer: 0.91 (t, J ¼ 7.1 Hz,
3H), 1,67 (s, 3H), 3.55–4.29 (m, 2H), 4.84 (s, 2H), 6.33 (s, 1H), 7.33–
7.95 (m, 12H), 9.02 (s, 1H), 9.79 (s, 1H); 13C-NMR (400 MHz,
DMSO-d6), d (ppm): E-isomer: 14.5, 29.2, 62.5, 75.2, 77.8, 122.9,
123.3, 126.5, 126.7, 127.8, 128.4, 128.5, 128.7, 128.9, 129.2, 132.5,
133.1, 136.4, 143.3, 152.3, 156.2. Z-isomer: 15.5, 32.2, 66.0, 75.2,
77.9, 123.0, 123.5, 126.3, 126.6, 127.9, 128.3, 128.4, 128.6, 128.7,
129.2, 132.5, 133.1, 136.4, 143.3, 152.3, 156.2; anal. calcd.
for C23H25N3O4: Calcd. C 67.80%, H 6.18%, N 10.31%; found
C 67.67%, H 6.08%, N 10.38%.
Ethyl (1E/Z)-N-[(4-chlorobenzyl)carbamoyl]-2-
(3,4-dichlorophenyl)-2-hydroxypropanehydrazonoate 5g
Colorless solid, yield: 80%; mp: 180.68C; IR nmax (KBr) cmꢀ1: 3423,
1
–
–
3400, 3300 (NH, OH), 1647 (C O, C N); ratio E/Z ¼ 92:8; H-NMR
–
–
(400 MHz, DMSO-d6), d (ppm): E-isomer: 1.25 (t, J ¼ 7.0 Hz, 3H),
1.62 (s, 3H), 4.07–4.13 (m, 2H), 4.14–4.40 (m, 2H), 6.33 (s, 1H),
7.23–7.66 (m, 8H), 9.18 (s, 1H). Z-isomer: 1.03 (t, J ¼ 7.0 Hz, 3H),
1.64 (s, 3H), 3.61–4.06 (m, 2H), 4.14–4.40 (m, 2H), 6.33 (s, 1H),
7.23–7.66 (m, 8H), 8.81 (s, 1H); 13C-NMR (400 MHz, DMSO-d6),
d (ppm): E-isomer: 14.4, 28.8, 42.2, 62.7, 76.6, 125.3, 126.6,
131.0, 128.4, 129.1, 130.5, 131.4, 131.3, 140.3, 145.5, 151.8,
155.7. Z-isomer: 15.4, 31.4, 42.3, 66.0, 74.8, 125.6, 127.0, 130.9,
128.5, 129.2, 129.9, 131.4, 131.3, 140.2, 147.2, 149.7, 156.1; anal.
calcd. for C19H20Cl3N3O3: Calcd. C 51.31%, H 4.53%, N 9.45%;
found C 51.13%, H 4.70%, N 9.30%.
Ethyl (1E/Z)-2-(3,4-dichlorophenyl)-2-hydroxy-N-
(methylcarbamoyl)propanehydrazonoate 5d
Colorless solid, yield: 81%; mp: 173.88C; IR nmax (KBr) cmꢀ1: 3430,
–
–
3369, 3318, 3298, 3219 (NH, OH), 1654 (C O), 1648 (C N); ratio
–
–
E/Z ¼ 60:40; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 1.25
(t, J ¼ 7.0 Hz, 3H), 1.60 (s, 3H), 2.58 (d, 3H), 4.05–4.10 (m, 2H),
6.40–6.43 (q, 1H), 7.22 (s, 1H), 7.60–7.65 (m, 3H), 9.02 (s, 1H).
Z-isomer: 1.02 (t, J ¼ 7.0 Hz, 3H), 1.63 (s, 3H), 2.68 (d, 3H), 3.59–
4.16 (m, 2H), 6.30 (s, 1H), 6.67–6.71 (q, 1H), 7.34–7.37 (m, 3H), 8.61
(s, 1H); 13C-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer: 14.4,
26.4, 28.6, 62.5, 76.5, 125.3, 126.8, 131.0, 130.4, 131.3, 145.6,
151.4, 156.1. Z-isomer: 15.4, 26.5, 31.4, 66.0, 74.8, 125.6, 127.0,
130.9, 129.9, 131.3, 147.2, 149.3, 156.5; anal. calcd.
for C13H17Cl2N3O3: Calcd. C 46.72%, H 5.13%, N 12.57%; found
C 46.43%, H 5.18%, N 12.59%.
Ethyl (1E/Z)-N-(ethylcarbamothioyl)-2-hydroxy-2-
(naphthalen-2-yl)propanehydrazonoate 6a
Colorless solid, yield: 84%; Mp: 118.38C; IR nmax (KBr) cmꢀ1: 3358,
–
–
3325, 3140, 3123 (NH, OH), 1637 (C N), 1128 (C S); ratio
–
–
E/Z ¼ 85:15; 1H-NMR (400 MHz, DMSO-d6), d (ppm): E-isomer:
1.04 (t, J ¼ 7.1 Hz, 3H), 1.28 (t, J ¼ 7.0 Hz, 3H), 1.74 (s, 3H),
3.39–3.51 (m, 2H), 4.15–4.21 (q, 2H), 7.33 (s, 1H), 7.50–7.98
(m, 7H), 7.79 (t, J ¼ 6.0 Hz, 1H), 10.54 (s, 1H). Z-isomer: 0.94
(t, J ¼ 7.1 Hz, 3H), 1.17 (t, J ¼ 7.0 Hz, 3H), 1.75 (s, 3H), 3.55–
3.71 (m, 2H), 4.27–4.35 (q, 2H), 6.43 (s, 1H), 7.50–7.98 (m, 7H),
8.24 (t, J ¼ 6.0 Hz, 1H), 9.18 (s, 1H); 13C-NMR (400 MHz, DMSO-d6),
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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764
M. Khankischpur et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 755–764
d (ppm): E-isomer: 14.4, 15.1, 28.9, 38.1, 63.1, 77.6, 123.0, 123.3,
126.6, 126.8, 127.8, 128.5, 128.6, 132.6, 132.9, 141.5, 154.6, 175.4.
Z-isomer: 15.0, 15.4, 32.1, 38.9, 66.5, 75.6, 123.2, 123.4, 126.3,
126.6, 127.9, 128.4, 128.5, 132.5, 133.1, 142.9, 151.9, 176.9; anal.
calcd. for C18H23N3O2S: Calcd. C 62.58%, H 6.71%, N 12.16%;
found C 62.41%, H 6.73%, N 12.15%.
Remarkable antiplasmodial activity was ascertained for com-
pounds 4r, 5d and 4q with IC50 values of 0.6, 0.85 and 1.1 mM,
making these a-hydroxy hydrazonates promising candidates
for further drug-design.
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In conclusion, novel a-hydroxy hydrazonates have been pre-
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