Synthesis and antiplasmodial activity of 4-alkylidene(arylidene)hydrazono- 1,3-oxazinan-2-ones and 3-hydroxy-N-alkylidene(arylidene)propanehydrazonamides

Article abstract of DOI:10.1071/CH10052

Previously unreported 6-substituted 4-alkylidene(arylidene)hydrazono-1,3- oxazinan-2-ones and a series of open-chained 3-hydroxy-N′- alkylidene(arylidene)propanehydrazonamides were synthesized and evaluated for their in vitro antiplasmodial activity. The

Full text of DOI:10.1071/CH10052

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2010, 63, 1430–1436
www.publish.csiro.au/journals/ajc
Synthesis and Antiplasmodial Activity of 4-Alkylidene
(arylidene)hydrazono-1,3-oxazinan-2-ones and 3-Hydroxy-
Nꢀ-alkylidene(arylidene)propanehydrazonamides
Mehdi Khankischpur,A Rolf D. Walter,B and Thomas KurzC,D
AInstitute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany.
BBernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
CInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany.
DCorresponding author. Email: Thomas.Kurz@uni-duesseldorf.de
Previously unreported 6-substituted 4-alkylidene(arylidene)hydrazono-1,3-oxazinan-2-ones and a series of open-chained
3-hydroxy-Nꢀ-alkylidene(arylidene)propanehydrazonamides were synthesized and evaluated for their in vitro antiplas-
modial activity. The most active 3-hydroxy-Nꢀ-alkylidene(arylidene)propanehydrazonamide exhibits potent in vitro
antiplasmodial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum and demonstrates an
IC50 value of 0.2 μM.
Manuscript received: 28 January 2010.
Manuscript accepted: 21 April 2010.
O
Introduction
NH2
N
O
NH
N
The amidrazone functionality is present in various biologi-
cally active compounds and represents an important structural
motif in drug design and agro chemistry. Amidrazones have
for instance been described as insecticides,[1] fungicides,[2]
and lipoxygenase inhibitors.[3,4] In this respect, consider-
able attention has been devoted to arylidene derivatives
of heteroarylcarbox-amidrazones, especially due to their
potent antimycobacterial activity[5,6] and selective action on
Gram-positive bacteria.[7] Interestingly, certain Nꢀ-arylidene-
pyridine-2-carboxamidrazones of type I demonstrate potent
antiplasmodialactivity, asreportedbyGokhaleandcoworkers.[8]
Recently, oxazolidin-2-ones of type II have been identified as
antiplasmodial agents.[9] Both lead compounds I and II share
the amidrazone moiety linked with an alkylidene or arylidene
group as a common structural element (Fig. 1).
N
N
N
N
I
II
O
O
OH
NH
NH2
RЈ
RЈ
N
N
N
N
R
R
RЉ
RЉ
4
6
Fig. 1. Lead structures (I, II) and title compounds (4, 6).
Over the past years, we have studied the synthesis and
reactivity of β-hydroxy imidates (1) and 4-ethoxy-5,6-dihydro-
2H-1,3-oxazin-2-ones(2).[10] Incontinuationoftheseefforts, we
have now investigated the synthesis and antiplasmodial proper-
ties of 4-alkylidene(arylidene)hydrazono-1,3-oxazinan-2-ones
(4) and their open-chained analogues (6). Title compounds 4,
in which the amidrazone group is partly included in the 1,3-
oxazinan ring, can be considered as ring extended analogues
of compound II, whereas target compounds 6 bear a structural
resemblance to compound I.
respectively.[10] Substrates 2 are accessible by cyclic carbonyla-
tion of β-hydroxy imidates 1 using CDT [1,1ꢀ-carbonyldi-
(1,2,4-triazole)] as the carbonylating agent.[10] The treatment
of4-ethoxy-5,6-dihydro-2H-1,3-oxazin-2-ones2withhydrazine
hydrate furnished the corresponding 4-hydrazono-1,3-oxazinan-
2-ones (3a–d) as solid compounds in 91–99% yield. Due to their
unstable nature, the structures of semicyclic amidrazones 3 were
only elucidated by IR spectroscopy [νmax 1705–1725 (C=O),
1670–1690 (C=N) cm−1] andTLC. Subsequent condensation of
compounds 3 with various aldehydes and ketones afforded the so
far unknown 6-substituted 4-alkylidene(arylidene)-hydrazono-
1,3-oxazinan-2-ones (4a–h) in 65–86% yield after recrystalliza-
tion from appropriate solvents (Table 1 and Scheme 1).
Results and Discussion
Our retrosynthetic analysis led to β-hydroxy imidates 1 and
4-ethoxy-5,6-dihydro-2H-1,3-oxazine-2-ones 2 as suitable inter-
mediates for the preparation of target compounds 4 and 6,
Heterocycles 4 demonstrate strong (C=N) and (C=O)
absorption bands at 1648–1661 and at 1718–1739 cm−1, respec-
tively, in their IR spectra. In accordance with 1D and 2D proton
© CSIRO 2010
10.1071/CH10052
0004-9425/10/101430

Synthesis and Antiplasmodial Activity
1431
Table 1. 4-Hydrazono-1,3-oxazinan-2-ones (3a–d) and 4-alkylidene
(arylidene)hydrazono-1,3-oxazinan-2-ones (4a–h)
OH NH
OH NH2
(i)
NH2
R1
O
R1
N
1
5
Entry
R1
R2
R3
Yield [%]
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
Ph
4-F-Ph
4-Cl-Ph
1-Naphthyl
Ph
95
91
98
99
65
79
67
64
66
86
72
73
(iii)
(ii)
55–79%
44%
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
4-F-Ph
4-F-Ph
NH2
OH
R2
CH3
CH3
-(CH2)5-
N
R1
N
4-Cl-Ph
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
R3
Ph
H
6
CH3
CH3
4g
4h
-(CH2)4-
-(CH2)5-
Scheme 2. Synthesis of 3-hydroxy-Nꢀ-alkylidene(arylidene)-propane-
hydrazonamides (6a–k). Reagents and conditions: (i) 1 equiv. N2H4xH2O,
DCM, 0◦C; (ii) 1.5 equiv. R1R2CO, DCM, RT; (iii) 1 equiv. cyclohexanone
hydrazone, DCM, RT.
O
Table2. 3-Hydroxy-Nꢀ-alkylidene(arylidene)propanehydrazon-amides
OH NH
O
N
(i)
(6a–k)
R1
R1
65–71%
O
O
1
2
Entry
R1
R2
R3
Yield [%]
6a
6b
6c
6d
6e
6f
6g
6h
6i
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
2-Naphthyl
3-Br,4-F-Ph
-(CH2)4-
-(CH2)5-
-(CH2)2O(CH2)2-
-(CH2)2S(CH2)2-
55
65
66
71
63
55
68
70
79
74
44
(ii)
91–99%
O
O
CH3
CH3
H
H
H
H
Cyclopropyl
Ph
4-Cl-Ph
1-Naphthyl
O
NH
O
NH
(iii)
R2
R3
R1
N
N
R1
65–86%
NH2
N
4
3
6j
6k
-(CH2)5-
-(CH2)5-
Scheme 1. Synthesis of 4-alkylidene(arylidene)hydrazono-1,3-oxazinan-
2-ones (4a–h). Reagents and conditions: (i) CDT, DCM, 0◦C; (ii) 2 equiv.
N2H4xH2O, DCM, 0◦C; (iii) 2 equiv. R1R2CO, DCM, RT.
NMR experiments, compounds 4a–h have been obtained as
mixtures of E and Z isomers.
Biological Activity
The in vitro antiplasmodial activity of compounds 4 and 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.[13] IC50 values
as well as the inhibition of parasite growth at 5 μM have been
determined. The antimalarial drug pyrimethamine (Pyr) was
used as reference compound (Tables 3 and 4).
The open-chained target compounds 6 were accessible start-
ing from β-hydroxy imidates 1 (Scheme 2). Hydrazinolysis of
compounds 1, according to a modified literature procedure,[11]
provided rather unstable β-hydroxy amidrazones 5, which were
isolated as solid intermediates. Because of their instability,
intermediates 5 were directly converted into 3-hydroxy-Nꢀ-
alkylidene(arylidene)propanehydrazonamides (6a–j) by treat-
ment with the appropriate aldehydes or ketones, in overall
yields of 55–79%. Only target compound 6k was prepared by
direct condensation of cyclohexanone hydrazone[12] with the
appropriate imidate in 44% yield (Table 2).[10]
Compounds 6 display either one broad or two sharp and sep-
arated (C=N) absorption bands between 1594 and 1655 cm−1
in their IR spectra. According to NMR experiments, compounds
6a–e,j,k were isolated as Z isomers. In order to elucidate the
structure of compounds 6f–i and in particular the configura-
tions at both C=N double bonds, an X-ray structure analysis
was performed.
Unexpectedly, mostoftheevaluated3-hydroxy-Nꢀ-alkylidene
(arylidene)propanehydrazonamides 6 were significantly more
active as heterocycles 4. Our results demonstrate that a free
hydroxyl group and an amino group are necessary for potent
invitroantiplasmodialactivity(Table3). Derivatives6g–i, which
contain 1-naphthyl-substituents and different arylidene groups,
are the most active representatives in this screening.
Conclusion
In summary, we have developed the first synthetic method
for the preparation of 4-alkylidene(arylidene)hydrazono-1,
3-oxazinan-2-ones(4), and3-hydroxy-Nꢀ-alkylidene(arylidene)-
propanehydrazonamides (6). Only 3-hydroxy-Nꢀ-alkylidene-
(arylidene)propanehydrazonamides 6 demonstrate antiplas-
modial properties. The most active compound 6g displays
promising in vitro antiplasmodial activity against the
The X-ray crystal structure of compound 6f clearly shows a
Z configuration at the C13=N2 double bond and an E config-
uration with regard to the C14=N3 double bond (Fig. 2). The
structure of target compounds 4 and 6 were determined by IR,
1H, 13C NMR spectroscopy, and elemental analysis.

1432
M. Khankischpur, R. D. Walter, and T. Kurz
O1
N1
C10
C1
C9
N3
C11
N2
C13
C12
C8
C17
C14
C2
C15
C7
C6
C3
C4
C16
C5
Fig. 2. X-ray crystal structure of compound 6f.
Table 3. Inhibition of P. falciparum growth [%] at 5 μM
Experimental
General
Compound
Inhibition of P. falciparum growth
Melting points (uncorrected) were determined on an Electrother-
mal 9100 melting point apparatus. Elemental analyses were
carried out with a Heraeus CHN-O-Rapid instrument. IR spectra
were recorded on an ATI Genesis Series FT-IR spectrome-
ter. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a Bruker AMX 400 spectrometer using tetra-
methylsilane as an internal standard and [D6]DMSO as solvent.
Crystallographic data for compound 6f have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 762811.
Inhibition [%]
n
4a
4b
4c
4d
4e
4f
4g
4h
6a
6b
6c
6d
6e
6f
6g
6h
0
0
0
15
17
10
0
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
0
93
46
23
30
37
38
96
93
93
10
15
80
General Procedure for the Synthesis of 3a–d
Theappropriate4-ethoxy-5,6-dihydro-2H-1,3-oxazine-2-one[10]
2 (2 mmol), dissolved in dry dichloromethane (5 mL), was
added dropwise to a stirred ice-cooled solution of hydrazine
hydrate (0.2 mL, 4 mmol) in dry dichloromethane (5 mL) within
5–10 min. The reaction mixture was stirred at 5◦C for 1 h and
then kept at room temperature for additional 4 h. The prod-
ucts were separated by filtration and washed with diethyl ether.
The structures of 4-hydrazono-1,3-oxazinan-2-ones 3a–d were
confirmed by IR spectroscopy.All 4-hydrazono-1,3-oxazinan-2-
ones were used for the synthesis of compounds 4 without further
purification.
6i
6j
6k
Pyrimethamine
Table 4. IC50 values of selected compounds 6 against P. falciparum
4-Hydrazinylidene-6-phenyl-1,3-oxazinan-2-one 3a
Colourless solid (95%), mp 134.5◦C. νmax (KBr)/cm−1 3338,
3264, 1714, 1685. m/z (EI) 205 (M)+; Calc. for C10H11N3O2:
205.2.
Compound
Activity against P. falciparum
IC50 [μM]
n
s.e.m.
6a
6g
6h
6i
3.0
0.2
0.56
0.51
0.07
4
4
6
6
8
0.23
0.05
0.19
0.20
0.03
6-(4-Fluorophenyl)-4-hydrazinylidene-1,3-oxazinan-
2-one 3b
Colourless solid (91%), mp 146.0◦C. νmax (KBr)/cm−1 3353,
3291, 3196, 1723, 1684. m/z (EI) 223 (M)+; Calc. for
C10H10FN3O2: 223.2.
Pyrimethamine
6-(4-Chlorophenyl)-4-hydrazinylidene-1,3-oxazinan-
2-one 3c
chloroquine-sensitive 3D7 strain of P. falciparum and exhibits
an IC50 value of 0.2 μM. Further investigations regarding
the structure-activity relationships within this novel class of
antiparasitic compounds are intended.
Colourless solid (98%), mp 220.0◦C (decomposition). νmax
(KBr)/cm−1 3379, 3217, 1708, 1674. m/z (EI) 239 (M)+; Calc.
for C10H10ClN3O2: 239.6.

Synthesis and Antiplasmodial Activity
1433
4-Hydrazinylidene-6-(naphthalen-1-yl)-1,3-oxazinan-
2-one 3d
(4E/Z)-6-(4-Fluorophenyl)-4-(propan-
2-ylidenehydrazinylidene)-1,3-oxazinan-2-one 4c
Colourless solid, yield (99%), mp 149.3◦C. νmax (KBr)/cm−1
3293, 3194, 1717, 1687. m/z (EI) 255 (M)+; Calc. for
C10H11N3O2: 255.3.
Colourless solid (67%), mp 142.5◦C. Ratio E/Z = 75:25.
νmax (KBr)/cm−1 3227, 1724, 1653, 1624. E isomer: δH
(400 MHz, [D6]DMSO) 1.91 (s, 3H, CH3), 1.99 (s, 3H, CH3),
2.90 (dd, J 16.1, 3.2, 1H, COCHCN), 3.11 (dd, J 16.0, 11.2, 1H,
COCHCN), 5.66 (dd, J 10.8, 2.9, 1H, CH), 7.25–7.30 (m, 2H,
ArH), 7.52–7.57 (m, 2H, ArH), 9.67 (br s, 1H, NH). Z isomer:
δH (400 MHz, [D6]DMSO) 1.93 (s, 6H C(CH3)2), 2.84–2.90
(m, 1H, COCHCN), 3.45 (dd, J 16.9, 3.2, 1H, COCHCN), 5.53
(dd, J 11.3, 2.9, 1H, CH), 7.23–7.31 (m, 2H, ArH), 7.48–7.59
(m, 2H, ArH), 10.56 (br s, 1H, NH). δC (100 MHz, [D6]DMSO)
18.2 (CH3), 25.2 (CH3), 25.2 (CH3), 29.0 (COCH2CN), 32.9
(COCH2CN), 75.1(CH), 76.0(CH), 115.8(d, 2JC-F 21.4,ArCH),
General Procedure for the Synthesis of 4a–h
To a suspension of the respective 4-hydrazono-1,3-oxazinan-
2-one 3 (1.5 mmol) in dry dichloromethane, the appropriate
aldehyde or ketone (3 mmol) was added and the reaction mix-
ture was stirred at room temperature for 12 h. The solvent was
then removed under reduce pressure and the remaining residue
was purified by filtration through a short silica gel column
(5 cm) with EtOAc–n-hexane (1:1) as the eluent. Crystalliza-
tion from Et2O/n-hexane provided 4a–h as solid compounds.
Recrystallization from EtOAc/n-hexane provided analytically
pure products.
3
4
129.1 (d, JC-F 8.4, ArCH), 134.4 (d, JC-F 3.0, ArC), 134.7
(d, 4JC-F 2.3, ArC), 146.8 (NC=N), 149.9, 151.4 (C=O), 154.1
1
1
(NC=N), 162.1 (d, JC-F 244.9, ArC), 163.7 (d, JC-F 244.1,
ArC), 164.6 (C=N). Anal. Calc. for C13H14FN3O2: C 59.31,
H 5.36, N 15.96. Found: C 59.53, H 5.61, N 15.87%.
(4E/Z)-6-Phenyl-4-(tetrahydro-4H-pyran-
4-ylidenehydrazinylidene)-1,3-oxazinan-2-one 4a
(4E/Z)-6-(4-Chlorophenyl)-4-(cyclohexylidene-
hydrazinylidene)-1,3-oxazinan-2-one 4d
Colourless solid (65%), mp 172.0◦C. Ratio E/Z = 99:1.
νmax (KBr)/cm−1 3249, 1733, 1648, 1619. E isomer: δH
(400 MHz, [D6]DMSO) 2.43 (t, J 5.6, 2H, CH2CH2O), 2.52–
2.72 (m, 2H, CH2CH2O), 2.91 (dd, J 16.1, 3.0, 1H, COCHCN),
3.11 (dd, J 16.3, 10.8, 1H, COCHCN), 3.63 (t, J 5.8, 2H,
CH2CH2O), 3.77 (t, J 5.6, 2H, CH2CH2O), 5.66 (dd, J 10.8,
3.0, 1H, CH), 7.36–7.53 (m, 5H, ArH), 9.85 (br s, 1H,
NH). E isomer: δC (100 MHz, [D6]DMSO) 29.3 (CH2CH2O),
32.6 (COCH2CN), 35.4 (CH2CH2O), 66.5 (CH2CH2O), 67.7
(CH2CH2O), 76.2 (CH), 126.3, 128.6 (ArCH), 137.7 (ArC),
147.6 (NC=N), 149.5 (C=O), 164.7 (C=N). Anal. Calc. for
C15H17N3O3: C 62.71, H 5.96, N 14.62. Found: C 62.81, H 6.09,
N 14.63%. The signals of the corresponding Z isomer could not
be analyzed because of their weak intensity in the NMR spectra.
Colourless solid (64%), mp 165.5◦C. Ratio E/Z = 45:55.
νmax (KBr)/cm−1 3223, 1718, 1655. E isomer: δH (400 MHz,
[D6]DMSO)1.47–1.73(m, 6H, (CH2)3), 2.31(t, J6.1, 2H, CH2),
2.46–2.61 (m, 2H, CH2), 2.91 (dd, J 16.1, 3.3, 1H, COCHCN),
3.07 (dd, J 16.1, 11.0, 1H, COCHCN), 5.67 (dd, J 10.8, 3.3, 1H,
CH), 7.47–7.54 (m, 4H, ArH), 9.70 (br s, 1H, NH). Z isomer: δH
(400 MHz, [D6]DMSO) 1.45–1.74 (m, 6H, (CH2)3), 2.24 (t, J
6.0, 2H, CH2), 2.46–2.61 (m, 2H, CH2), 2.87 (dd, J 16.8, 11.3,
1H, COCHCN), 3.49 (dd, J 16.9, 3.4, 1H, COCHCN), 5.55 (dd,
J 11.2, 3.4, 1H, CH), 7.45–7.55 (m, 4H, ArH), 10.55 (br s, 1H,
NH). δC (100 MHz, [D6]DMSO) 25.3, 25.4, 26.1, 27.0, 27.1,
27.6, 27.6 (C4H6), 28.5, 32.6 (COCH2CN), 35.0, 35.2 (CH2),
74.6, 75.5 (CH), 128.2, 128.2, 128.6 (ArCH), 133.2, 133.3,
136.8, 137.1 (ArC), 147.0 (NC=N), 149.3, 150.9 (C=O), 154.1
(NC=N), 168.7, 169.5 (C=N). Anal. Calc. for C16H18ClN3O2:
C 60.09, H 5.67, N 13.14. Found: C 59.79, H 5.77, N 13.06%.
(4E/Z)-6-(4-Fluorophenyl)-4-(tetrahydro-4H-pyran-
4-ylidenehydrazinylidene)-1,3-oxazinan-2-one 4b
Colourless solid (79%), mp 178.0◦C. Ratio E/Z = 51:49.
νmax (KBr)/cm−1 3248, 1719, 1655. E isomer: δH (400 MHz,
[D6]DMSO) 2.44 (t, J 5.6, 2H, CH2CH2O), 2.63 (td, J 5.8,
2.5, 2H, CH2CH2O), 2.89 (dd, J 16.1, 3.3, 1H, COCHCN),
3.12 (dd, J 16.1, 11.3, 1H, COCHCN), 3.61–3.65 (m, 2H,
CH2CH2O), 3.77 (t, J 5.9, 2H, CH2CH2O), 5.67 (dd, J 11.0,
3.0, 1H, CH), 7.23–7.32 (m, 2H, ArH), 7.49–7.57 (m, 2H, ArH),
9.82 (br s, 1H, NH). Z isomer: δH (400 MHz, [D6]DMSO)
2.36 (t, J 5.6, 2H, CH2CH2O), 2.65–2.75 (m, 2H, CH2CH2O),
2.93 (dd, J 16.9, 11.2, 1H, COCHCN), 3.51 (dd, J 16.9, 3.4,
1H, COCHCN), 3.63–3.67 (m, 2H, CH2CH2O), 3.73 (t, J 5.6,
2H, CH2CH2O), 5.55 (dd, J 11.4, 3.1, 1H, CH), 7.23–7.31 (m,
2H, ArH), 7.49–7.57 (m, 2H, ArH), 10.61 (br s, 1H, NH). δC
(100 MHz, [D6]DMSO) 28.6 (COCH2CN), 29.2 (CH2CH2O),
29.4 (CH2CH2O), 32.6 (COCH2CN), 35.3 (CH2CH2O),
35.5 (CH2CH2O), 66.4 (CH2CH2O), 66.4 (CH2CH2O), 67.6
(CH2CH2O), 67.7 (CH2CH2O), 74.6 (CH), 75.6 (CH), 115.4 (d,
(4E/Z)-4-(Benzylidenehydrazinylidene)-6-(naphthalen-
1-yl)-1,3-oxazinan-2-one 4e
Colourless solid (66%), mp 195.8◦C. Ratio E/Z = 62:38.
νmax (KBr)/cm−1 3282, 1721, 1648. E isomer: δH (400 MHz,
[D6]DMSO) 3.10 (dd, J 16.1, 2.2, 1H, COCHCN), 3.36–3.43
(m, 1H, COCHCN), 6.54–6.59 (m, 1H, CH), 7.41 (br s, 1H,
ArH), 7.48 (br s, 2H, ArH), 7.58–7.66 (m, 3H, ArH), 7.73 (d, J
6.9, 2H, ArH), 8.01 (t, J 7.4, 2H, ArH), 8.11 (d, J 6.0, 1H, ArH),
8.24 (d, J 8.2, 1H,ArH), 8.47 (s, 1H, NCH), 10.80 (br s, 1H, NH).
Z isomer: δH (400 MHz, [D6]DMSO) 3.30 (dd, J 17.0, 11.3, 1H,
COCHCN), 3.91 (dd, J 16.9, 2.4, 1H, COCHCN), 6.47 (dd, J
10.9, 1.7, 1H, CH), 7.40 (br s, 1H, ArH), 7.46 (br s, 2H, ArH),
7.58–7.66 (m, 3H, ArH), 7.77 (d, J 6.6, 2H, ArH), 8.01 (t, J 7.4,
2H, ArH), 8.11 (d, J 6.0, 1H, ArH), 8.27 (d, J 8.8, 1H, ArH), 8.46
(s, 1H, NCH), 11.00 (br s, 1H, NH). δC (100 MHz, [D6]DMSO)
28.2, 32.1 (COCH2CN), 72.5, 73.1 (CH), 123.3, 123.4, 123.9,
124.1, 125.3, 125.4, 126.0, 126.0, 126.7, 126.7, 127.8, 128.4,
128.7, 128.7, 128.9, 129.3, 129.3 (ArCH), 130.0, 130.5, 130.7,
133.0, 133.3, 133.3, 134.4, 134.4 (ArC), 149.8 (NC=N), 151.1,
151.6 (C=O), 157.1, 158.2 (NCH), 159.0 (C=N). Anal. Calc.
for C21H17N3O2: C 73.45, H 4.99, N 12.24. Found: C 73.09,
H 5.13, N 12.17%.
3
3
2JC-F 22.0, ArCH), 128.6 (d, JC-F 8.1, ArCH), 128.7 (d, JC-F
8.1, ArCH), 133.9 (d, 4JC-F 2.9, ArC), 134.2 (d, 4JC-F 2.9, ArC),
147.5 (NC=N), 149.4, 150.9 (C=O), 155.1 (NC=N), 161.7 (d,
1
1JC-F 244.3, ArC), 163.3 (d, JC-F, 245.0, ArC), 164.2, 164.7
(C=N).Anal. Calc. for C15H16FN3O3: C 59.01, H 5.28, N 13.76.
Found: C 58.80, H 5.38, N 13.53%.

1434
M. Khankischpur, R. D. Walter, and T. Kurz
(4E/Z)-6-(Naphthalen-1-yl)-4-(propan-
2-ylidenehydrazinylidene)-1,3-oxazinan-2-one 4f
151.7 (C=O), 154.9 (NC=N), 169.0, 170.0 (C=N). Anal. Calc.
for C20H21N3O2: C 71.62, H 6.31, N 12.53. Found: C 71.51,
H 6.51, N 12.33%.
Colourless solid (86%), mp 147.0◦C. Ratio E/Z = 50:50.
νmax (KBr)/cm−1 3364, 1739, 1649, 1624. E isomer: δH
(400 MHz, [D6]DMSO) 1.94 (s, 3H, CH3), 2.02 (s, 3H, CH3),
3.04 (dd, J 16.1, 3.3, 1H, COCHCN), 3.28 (dd, J 16.1, 10.8,
1H, COCHCN), 6.48 (dd, J 10.9, 3.1, 1H, CH), 7.55–7.61 (m,
3H, ArH), 7.70 (d, J 7.0, 1H, ArH), 7.98–8.02 (m, 2H, ArH),
8.21 (d, J 8.3, 1H, ArH), 9.74 (br s, 1H, NH). Z isomer: δH
(400 MHz, [D6]DMSO) 1.91 (s, 3H, CH3), 1.95 (s, 3H, CH3),
3.08 (d, J 11.3, 1H, COCHCN), 3.61 (dd, J 16.9, 3.4, 1H,
COCHCN), 6.36 (dd, J 10.7, 3.1, 1H, CH), 7.55–7.66 (m, 4H,
ArH), 7.96–8.01 (m, 2H, ArH), 8.19 (d, J 6.8, 1H, ArH), 10.63
(br s, 1H, NH). δC (100 MHz, [D6]DMSO) 18.3, 25.2 (CH3),
28.3, 32.3 (COCH2CN), 72.7, 73.6 (CH), 123.7, 123.7, 124.2,
124.2, 125.7, 125.7, 126.4, 126.4, 127.1, 127.1, 129.1, 129.1,
129.6, 129.7 (ArCH), 130.3, 130.4, 133.4, 133.7, 133.8 (ArC),
147.2 (NC=N), 150.1, 151.7 (C=O), 154.4 (NC=N), 163.7,
164.6 (C=N). Anal. Calc. for C17H17N3O2: C 69.14, H 5.80, N
14.23. Found: C 69.02, H 5.80, N 14.24%.
General Procedure for the Synthesis of 6a–k
The imidate bases were liberated from their hydrochlorides
as previously reported.[10] To a solution of the appropriate
β-hydroxy imidate 1 (2 mmol) in dry dichloromethane (15 mL)
hydrazine hydrate (0.1 mL, 2 mmol) was added at 5◦C. The
reaction mixture was allowed to stir at room temperature for
6 h. The solid intermediate 5 was separated by filtration, sus-
pended in anhydrous Et2O, filtered, and directly suspended in
dry dichloromethane. Next, the appropriate aldehyde or ketone
(3 mmol) was added and the reaction mixture was stirred at room
temperature for 10 h. After this time, the solvent was removed
under reduce pressure and the remaining residue was purified by
column chromatography using EtOAc/n-hexane (1:3) as the elu-
ent. Crystallization from Et2O/n-hexane provided compounds
6a–j as analytically pure products. Compound 6k was prepared
as follows: cyclohexanone hydrazone[12] (225 mg, 2 mmol) was
added to a solution of the corresponding imidate (2 mmol) in dry
dichloromethane (10 mL). The reaction mixture was stirred for
8 h at room temperature.After this time, the solvent was removed
under reduce pressure and the remaining residue was purified by
column chromatography using EtOAc/n-hexane (1:3) as the elu-
ent. Crystallization from Et2O/n-hexane provided compound 6k
as an analytically pure solid.
(4E/Z)-4-(Cyclopentylidenehydrazinylidene)-
6-(naphthalen-1-yl)-1,3-oxazinan-2-one 4g
Colourless solid (72%), mp 158.0◦C. Ratio E/Z = 57:43.
νmax (KBr)/cm−1 3383, 1734, 1661, 1624. E isomer: δH
(400 MHz, [D6]DMSO) 1.63–1.75 (m, 4H, (CH2)2), 2.27–2.45
(m, 4H, (CH2)2), 3.03(dd, J16.1, 3.2, 1H, COCHCN), 3.27(dd, J
16.0, 10.7, 1H, COCHCN), 6.47 (dd, J 10.8, 3.2, 1H, CH), 7.54–
7.63 (m, 3H, ArH), 7.69 (d, J 7.1, 1H, ArH), 7.95–8.02 ( m, 2H,
ArH), 8.19 (t, J 8.1, 1H, ArH), 9.72 (br s, 1H, NH). Z isomer: δH
(400 MHz, [D6]DMSO) 1.63–1.73 (m, 4H, (CH2)2), 2.27–2.45
(m, 4H, (CH2)2), 3.07 (dd, J 17.0, 10.7, 1H, COCHCN), 3.61
(dd, J 17.0, 3.6, 1H, COCHCN), 6.36 (dd, J 10.7, 3.6, 1H, CH),
7.54–7.66 (m, 4H, ArH), 7.96–8.02 (m, 2H, ArH), 8.19 (t, J 8.1,
1H, ArH), 10.6 (br s, 1H, NH). δC (100 MHz, [D6]DMSO) 24.5,
24.6, 24.6, 28.4 (C2H4), 29.7 (COCH2CN), 32.3 (C2H4), 33.1
(COCH2CN), 72.7, 73.6 (CH), 123.7, 123.7, 124.1, 124.2, 125.7,
125.7, 126.4, 126.4, 127.1, 127.1, 129.1, 129.5, 129.7 (ArCH),
130.3, 130.4, 133.4, 133.7, 133.8 (ArC), 146.8 (NC=N), 150.1,
151.6 (C=O), 154.5 (NC=N), 176.2, 176.9 (C=N). Anal. Calc.
for C19H19N3O2: C 71.01, H 5.96, N 13.07. Found: C 71.12,
H 6.11, N 13.03%.
(1Z)-Nꢀ-Cyclopentylidene-3-hydroxy-3-(naphthalen-
1-yl)propanehydrazonamide 6a
Colourless solid (55%), mp 116.1◦C. νmax (KBr)/cm−1 3454,
3319, 1647, 1618. δH (400 MHz, [D6]DMSO) 1.64–1.73 (m, 4H,
C2H4), 2.27–2.40 (m, 4H, C2H4), 2.47–2.53 (m, 1H, COCHCN),
2.62–2.66 (m, 1H, COCHCN), 5.70 (dd, J 8.9, 3.0, 1H, CH), 6.15
(br s, 1H, OH), 6.31 (br s, 2H, NH2), 7.46–7.57 (m, 3H, ArH),
7.70 (d, J 7.1, 1H, ArH), 7.82 (d, J 7.9, 1H, ArH), 7.90–7.96 (m,
1H, ArH), 8.21 (d, J 8.1, 1H, ArH). δC (100 MHz, [D6]DMSO)
24.2, 24.3, 28.8, 32.6 (C4H8), 41.2 (COCH2CN), 67.4 (CH),
122.9, 123.4, 125.3, 125.4, 125.8, 127.2, 128.5 (ArCH), 129.9,
133.2, 140.5 (ArC), 158.0 (C=N), 170.8 (NC=N). Anal. Calc.
for C18H21N3O: C 73.19, H 7.17, N 14.23. Found: C 73.47,
H 7.21, N 14.11%.
(1Z)-Nꢀ-Cyclohexylidene-3-hydroxy-3-(naphthalen-
1-yl)propanehydrazonamide 6b
(4E/Z)-4-(Cyclohexylidenehydrazinylidene)-
6-(naphthalen-1-yl)-1,3-oxazinan-2-one 4h
Colourless solid (65%), mp 109.5◦C. νmax (KBr)/cm−1 3375,
3193, 1649, 1618. δH (400 MHz, [D6]DMSO) 1.48–1.67 (m,
6H, C3H6), 2.24 (t, J 5.9, 2H, CH2), 2.52–2.54 (m, 3H,
CH2/COCHCN), 2.60–2.69 (m, 1H, COCHCN), 5.71 (dd, J
8.8, 3.3, 1H, CH), 5.98 (br s, 1H, OH), 6.27 (br s, 2H, NH2),
7.45–7.57 (m, 3H, ArH), 7.70 (d, J 7.0, 1H, ArH), 7.82 (d, J
8.0, 1H, ArH), 7.90–7.97 (m, 1H, ArH), 8.23 (d, J 8.0, 1H,
ArH). δC (100 MHz, [D6]DMSO) 26.1, 26.5, 27.6, 35.8 (C5H10),
42.0 (COCH2CN), 67.8 (CH), 123.3, 123.8, 125.7, 125.8, 126.2,
127.6, 128.9 (ArCH), 130.3, 133.6, 141.1 (ArC), 158.6 (C=N),
163.7 (NC=N). Anal. Calc. for C19H23N3O: C 73.76, H 7.49,
N 13.58. Found: C 73.48, H 7.48, N 13.44%.
Colourless solid (73%), mp 135.5◦C. Ratio E/Z = 55:45.
νmax (KBr)/cm−1 3366, 1735, 1648. E isomer: δH (400 MHz,
[D6]DMSO) 1.49–1.72 (m, 6H, C3H6), 2.35 (t, J 6.2, 2H, CH2),
2.52–2.64 (m, 2H, CH2), 3.03 (dd, J 16.0, 3.0, 1H, COCHCN),
3.28 (dd, J 16.0, 10.9, 1H, COCHCN), 6.48 (dd, J 10.9, 3.0,
1H, CH), 7.55–7.63 (m, 3H, ArH), 7.70 (d, J 7.1, 1H, ArH),
7.96–8.02 (m, 2H, ArH), 8.18–8.22 (m, 1H, ArH), 9.77 (br s,
1H, NH). Z isomer: δH (400 MHz, [D6]DMSO) 1.50–1.72 (m,
6H, C3H6), 2.18–2.23 (m, 2H, CH2), 2.52–2.63 (m, 2H, CH2),
3.06 (dd, J 17.0, 10.9, 1H, COCHCN), 3.64 (dd, J 17.0, 3.6, 1H,
COCHCN), 6.36 (dd, J 10.8, 3.2, 1H, CH), 7.55–7.67 (m, 4H,
ArH), 7.96–8.02 (m, 2H, ArH), 8.18–8.22 (m, 1H, ArH), 10.62
(br s, 1H, NH). δC (100 MHz, [D6]DMSO) 25.8, 25.8, 26.5, 26.5,
27.4, 27.5, 28.0, 28.0(C4H8), 28.3, 32.4(COCH2CN), 35.5, 35.6
(CH2), 72.7, 73.6 (CH), 123.7, 123.7, 124.2, 124.2, 125.7, 125.7,
126.4, 126.4, 127.1, 127.1, 129.1, 129.1, 129.5, 129.7 (ArCH),
130.3, 130.4, 133.4, 133.7, 133.9 (ArC), 148.0 (NC=N), 150.1,
(1Z)-3-Hydroxy-3-(naphthalen-1-yl)-Nꢀ-(tetrahydro-
4H-pyran-4-ylidene)propanehydrazonamide 6c
Colourless solid (66%), mp 133.1◦C. νmax (KBr)/cm−1 3367,
3199, 1654, 1625. δH (400 MHz, [D6]DMSO) 2.35 (t, J 5.6, 2H,

Synthesis and Antiplasmodial Activity
1435
CH2), 2.52–2.67 (m, 2H, COCH2CN), 2.63 (t, J 5.7, 2H, CH2),
3.61 (t, J 5.7, 2H, CH2O), 3.73 (t, J 5.6, 2H, CH2O), 5.72 (dd,
J 8.9, 3.6, 2H, CH), 5.87 (br s, 1H, OH), 6.35 (br s, 2H, NH2),
7.46–7.57 (m, 3H, ArH), 7.69 (d, J 7.1, 1H, ArH), 7.82 (d, J 8.1,
1H, ArH), 7.89–7.97 (m, 1H, ArH), 8.23 (d, J 7.9, 1H, ArH). δC
(100 MHz, [D6]DMSO) 28.9, 35.7 (CH2), 41.7 (COCH2CN),
66.6 (CH2O), 67.4 (CH), 67.9 (CH2O), 123.0, 123.4, 125.3,
125.3, 125.8, 127.2, 128.5 (ArCH), 129.9, 133.2, 140.7 (ArC),
158.5 (C=N), 158.6 (NC=N). Anal. Calc. for C18H21N3O2:
C 69.43, H 6.80, N 13.49. Found: C 69.22, H 6.83, N 13.44%.
(1Z)-3-Hydroxy-3-(naphthalen-1-yl)-Nꢀ-[(E)-
phenylmethylidene]propanehydrazonamide 6g
Colourless solid (68%), mp 110.9◦C. νmax (KBr)/cm−1 3455,
3315, 1623, 1594. δH (400 MHz, [D6]DMSO) 2.58 (dd, J 14.7,
9.2, 1H, COCHCN), 2.72 (dd, J 14.6, 3.5, 1H, COCHCN), 5.79
(d, J 8.8, 1H, CH), 5.86 (d, J 3.0, 1H, OH), 6.83 (br s, 2H,
NH2), 7.37–7.44 (m, 3H, ArH), 7.49–7.60 (m, 3H, ArH), 7.73
(d, J 7.0, 1H, ArH), 7.83 (d, J 7.5, 3H, ArH), 7.95 (d, J 7.8, 1H,
ArH), 8.27 (d, J 8.3, 1H,ArH), 8.32 (s, 1H, NCH). δC (100 MHz,
[D6]DMSO) 41.8 (COCH2CN), 67.4 (CH), 122.9, 123.4, 125.4,
125.9, 127.3, 127.4, 128.4, 128.6, 129.4 (ArCH), 129.8, 133.2,
135.7, 140.8 (ArC), 151.6 (CH=N), 161.7 (NC=N).Anal. Calc.
for C20H19N3O: C 75.69, H 6.03, N 13.24. Found: C 75.37,
H 6.16, N 13.20%.
(1Z)-3-Hydroxy-3-(naphthalen-1-yl)-Nꢀ-(tetrahydro-
4H-thiopyran-4-ylidene)propanehydrazonamide 6d
Colourless solid (71%), mp 138.2◦C. νmax (KBr)/cm−1 3374,
3197, 1654, 1612. δH (400 MHz, [D6]DMSO) 2.52–2.60 (m,
2H, CH2), 2.52–2.68 (m, 2H, COCH2CN), 2.60–2.69 (m, 2H,
CH2), 2.74–2.80 (m, 2H, CH2S), 2.84 (dd, J 7.5, 4.4, 2H, CH2S),
5.72 (dd, J 8.8, 3.7, 1H, CH), 5.85 (br s, 1H, OH), 6.36 (br s, 2H,
NH2), 7.45–7.58 (m, 3H, ArH), 7.69 (d, J 6.9, 1H, ArH), 7.82
(d, J 8.1, 1H, ArH), 7.89–7.97 (m, 1H, ArH), 8.23 (d, J 8.1, 1H,
ArH). δC (100 MHz, [D6]DMSO) 34.0, 35.1, 35.2, 42.9 (C4H8),
47.4 (COCH2CN), 73.1 (CH), 128.6, 129.1, 131.0, 131.0, 131.5,
132.9, 134.2 (ArCH), 135.6, 138.9, 146.4 (ArC), 164.2 (C=N),
165.9 (NC=N). Anal. Calc. for C18H21N3OS: C 66.03, H 6.46,
N 12.83. Found: C 66.24, H 6.53, N 12.71%.
(1Z)-Nꢀ-[(E)-(4-Chlorophenyl)methylidene]-3-hydroxy-
3-(naphthalen-1-yl)propanehydrazonamide 6h
Colourless solid (70%), mp 131.0◦C. νmax (KBr)/cm−1 3461,
3351, 1625, 1598. δH (400 MHz, [D6]DMSO) 2.58 (dd, J 14.2,
9.4, 1H, COCHCN), 2.72 (dd, J 14.6, 3.2, 1H, COCHCN), 5.79
(dd, J 8.6, 2.0, 1H, CH), 5.86 (br s, 1H, OH), 6.93 (br s, 2H,
NH2), 7.45–7.60 (m, 5H, ArH), 7.73 (d, J 6.9, 1H, ArH), 7.83
(d, J 8.1, 1H, ArH), 7.88 (d, J 8.4, 2H, ArH), 7.95 (d, J 7.9, 1H,
ArH), 8.27 (d, J 8.1, 1H,ArH), 8.32 (s, 1H, NCH). δC (100 MHz,
[D6]DMSO) 41.9 (COCH2CN), 67.4 (CH), 122.9, 123.4, 125.4,
125.9, 127.3, 128.5, 128.6, 129.0 (ArCH), 129.8, 133.2, 133.8,
134.7, 140.8 (ArC), 150.3 (CH=N), 162.1 (NC=N).Anal. Calc.
for C20H18ClN3O: C 68.28, H 5.16, N 11.94. Found: C 68.37,
H 5.12, N 11.83%.
(1Z)-3-Hydroxy-3-(naphthalen-1-yl)-Nꢀ-(propan-
2-ylidene)propanehydrazonamide 6e
Colourless solid (63%), mp 106.7◦C. νmax (KBr)/cm−1 3459,
3309, 1625. δH (400 MHz, [D6]DMSO) 1.90 (s, 3H, CH3), 1.93
(s, 3H, CH3), 2.48–2.54 (m, 1H, COCHCN), 2.60–2.69 (m, 1H,
COCHCN), 5.72 (dd, J 8.9, 3.3, 1H, CH), 6.02 (s, 1H, OH), 6.27
(br s, 2H, NH2), 7.47–7.57 (m, 3H, ArH), 7.70 (d, J 6.9, 1H,
ArH), 7.82 (d, J 8.1, 1H, ArH), 7.90–7.96 (m, 1H, ArH), 8.22 (d,
J 8.1, 1H, ArH). δC (100 MHz, [D6]DMSO) 17.9, 25.3 (CH3),
41.8 (COCH2CN), 67.8 (CH), 123.3, 123.8, 125.7, 125.8, 126.2,
127.6, 129.0 (ArCH), 130.3, 133.6, 141.0 (ArC), 158.2 (C=N),
158.3 (NC=N). Anal. Calc. for C16H19N3O: C 71.35, H 7.11,
N 15.60. Found: C 71.27, H 6.99, N 15.41%.
(1Z)-3-Hydroxy-3-(naphthalen-1-yl)-Nꢀ-[(E)-naphthalen-
1-ylmethylidene]propanehydrazonamide 6i
Colourless solid (79%), mp 166.7◦C. νmax (KBr)/cm−1 3483,
3367, 1610. δH (400 MHz, [D6]DMSO) 2.67 (dd, J 14.2, 9.7,
1H, COCHCN), 2.76–2.84 (m, 1H, COCHCN), 5.88 (d, J 8.4,
1H, CH), 5.95(brs, 1H, OH), 6.90(brs, 2H, NH2), 7.48–7.66(m,
6H,ArH), 7.79 (d, J 7.1, 1H,ArH), 7.85 (d, J 7.9, 1H,ArH), 7.92–
8.04 (m, 3H, ArH), 8.18 (d, J 6.8, 1H, ArH), 8.34 (d, J 8.4, 1H,
ArH), 8.84 (d, J 8.4, 1H,ArH), 9.07 (s, 1H, NCH). δC (100 MHz,
[D6]DMSO) 41.9 (COCH2CN), 67.5 (CH), 123.0, 123.5, 124.4,
125.4, 125.9, 126.0, 127.0, 127.1, 127.3, 128.5, 128.6, 129.7
(ArCH), 129.9, 130.6, 130.9, 133.3, 133.5, 140.9 (ArC), 151.2
(CH=N), 161.6 (NC=N). Anal. Calc. for C24H21N3O: C 78.45,
H 5.76, N 11.44. Found: C 78.55, H 5.43, N 11.28%.
(1Z)-Nꢀ-[(E)-Cyclopropylmethylidene]-3-hydroxy-
3-(naphthalen-1-yl)propanehydrazonamide 6f
Colourless solid (55%), mp 127.6◦C. νmax (KBr)/cm−1 3482,
3367, 1639, 1611. δH (400 MHz, [D6]DMSO) 0.65–0.71 (m,
2H, CHCH2CH2), 0.81–0.87 (m, 2H, CHCH2CH2), 1.57–1.70
(m, 1H, CHCH2CH2), 2.43–2.49 (m, 1H, COCHCN), 2.55–2.64
(m, 1H, COCHCN), 5.69 (dd, J 9.2, 3.0, 1H, CH), 5.86 (br s,
1H, OH), 6.38 (br s, 2H, NH2), 7.11 (d, J 8.1, 1H, NCH), 7.46–
7.57 (m, 3H, ArH), 7.69 (d, J 6.9, 1H, ArH), 7.82 (d, J 7.9, 1H,
ArH), 7.90–7.96 (m, 1H, ArH), 8.20 (d, J 8.1, 1H, ArH). δC
(100 MHz, [D6]DMSO) 6.3 (CHC2H4), 14.1 (CHC2H4), 41.9
(COCH2CN), 67.7 (CH), 123.3, 123.8, 125.8, 126.3, 127.6,
129.0 (ArCH), 130.2, 133.6, 141.2 (ArC), 159.5 (CH=N),
159.6 (NC=N). Anal. Calc. for C17H19N3O: C 72.57, H 6.81,
N 14.93. Found: C 72.31, H 6.81, N 14.86%. CCDC-762811
contains the supplementary crystallographic data for compound
6f. The data can be obtained from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
Fax: +44–1223–336033; E-mail: deposit@ccdc.cam.ac.uk, or
http://www.ccdc.cam.ac.uk/products/csd/request/.
(1Z)-Nꢀ-Cyclohexylidene-3-hydroxy-3-(naphthalen-
2-yl)propanehydrazonamide 6j
Colourless solid (74%), mp 119.6◦C. νmax (KBr)/cm−1 3453,
3326, 1619. δH (400 MHz, [D6]DMSO) 1.42–1.64 (m, 6H,
C3H6), 2.21 (t, J 6.1, 2H, CH2), 2.46 (t, J 6.4, 2H, CH2), 2.54 (d, J
6.6, 2H, COCH2CN), 5.10 (t, J 6.5, 1H, CH), 5.94 (br s, 1H, OH),
6.21(brs, 2H, NH2), 7.44–7.51(m, 2H,ArH), 7.54(dd, J8.6, 1.3,
1H, ArH), 7.84–7.90 (m, 4H, ArH). δC (100 MHz, [D6]DMSO)
26.0, 26.4, 27.6, 35.7 (C5H10), 42.5 (COCH2CN), 70.9 (CH),
124.5, 125.0, 125.9, 126.3, 127.8, 127.8, 128.1 (ArCH), 132.6,
133.1, 143.0 (ArC), 158.1 (C=N), 163.7 (NC=N). Anal. Calc.
for C19H23N3O: C 73.76, H 7.49, N 13.56. Found: C 73.85,
H 7.55, N 13.51%.

1436
M. Khankischpur, R. D. Walter, and T. Kurz
(1Z)-3-(3-Bromo-4-fluorophenyl)-Nꢀ-cyclohexylidene-
3-hydroxypropanehydrazonamide 6k
Acknowledgements
The authors thank Miss Isabelle Nevoigt for her valuable help in the prepara-
tion of the X-ray crystal structure. Moreover, the authors thank Mrs. Baerbel
Bergmann for performing the biological testing.
Colourless solid (44%), mp 105.5◦C. νmax (KBr)/cm−1 3362,
3210, 1655, 1617. δH (400 MHz, [D6]DMSO) 1.45–1.64 (m,
6H, C3H6), 2.21 (t, J 6.0, 2H, CH2), 2.37–2.48 (m, 4H,
CH2/COCH2CN), 4.94 (t, J 6.5, 1H, CH), 5.87 (br s, 1H, OH),
6.13 (br s, 2H, NH2), 7.30 (t, J 8.8, 1H, ArH), 7.39 (ddd, J
8.5, 5.1, 2.0, 1H, ArH), 7.65 (dd, J 7.0, 2.0, 1H, ArH). δC
(100 MHz, [D6]DMSO) 26.1, 26.5, 27.5, 27.6, 35.7 (C5H10),
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2
42.4 (COCH2CN), 69.6 (CH), 107.7 (d, JC-F 21.4, ArC),
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