Novel pyrrolinones as N-methyl-D-aspartate receptor antagonists

Article abstract of DOI:10.1016/j.ejmech.2004.11.010

A series of oximes, deriving from 2-arylidene-pyrroline-3,4-diones (7, 8, 22, 23) has been prepared. The presence of tautomers in their solutions has been established by spectroscopic means. The compounds reacted with diazomethane chiefly by N-methylation

Full text of DOI:10.1016/j.ejmech.2004.11.010

European Journal of Medicinal Chemistry 40 (2005) 391–400
www.elsevier.com/locate/ejmech
Original article
Novel pyrrolinones as N-methyl-D-aspartate receptor antagonists
Hermann Poschenrieder a, Hans-Dietrich Stachel a,*, Georg Höfner a, Peter Mayer b
a Department Pharmazie, Zentrum für Pharmaforschung, Universität München, Butenandtstr. 7, D-81377 München, Germany
b Department Chemie und Biochemie, Universität München, Butenandtstr. 9, D-81377 München, Germany
Received 29 July 2004; received in revised form 17 November 2004; accepted 19 November 2004
Available online 08 February 2005
Abstract
A series of oximes, deriving from 2-arylidene-pyrroline-3,4-diones (7, 8, 22, 23) has been prepared. The presence of tautomers in their
solutions has been established by spectroscopic means. The compounds reacted with diazomethane chiefly by N-methylation forming nitrones
(10, 11). The analogously prepared 2-arylidene-4-nitropyrrolin-3-ones (12, 13, 24, 25), formally derived from nitrotetramic acids, yielded
nitronic acid esters (14, 15, 26) upon reaction with diazomethane. The structures were elucidated by spectral evidence and—in the case of
compounds 10 and 20b—by X-ray diffraction analysis. The binding affinity of some of the new compounds toward the N-methyl-D-aspartate
(NMDA) (glycine site) receptor has been measured thus providing the basis for further structure–activity relationship studies. Oxime 8b
showed the highest binding potency (Ki = 9.2 µM).
© 2005 Elsevier SAS. All rights reserved.
Keywords: Tetramic acids; Azafulvenes; Nitrones; Nitronic acid esters; Glycine antagonists
1. Introduction
tives of 1 are the 3-nitrosopyrrol-2-ones 2 (Fig. 1) as well as
their nitro analogs, which may have a potential for use in
pain treatment [8]. The results of testing the affinity of these
compounds at the NMDA (glycine site) receptor revealed that
the stereochemistry of the side-chain substituents can play an
important role. Generally the fixation of the aryl substituent
trans to the ring nitrogen appears to be more favorable. All
these findings prompted us to synthesize compounds of gen-
eral formula 3 and their nitro analogs for further biological
The N-methyl-D-aspartate (NMDA) receptor is known to
mediate neuronal signaling and to affect gene expression as
well as the neuronal plasticity, outgrowth, and survival of cells
[1–3]. On the other hand, excessive stimulation of NMDA
receptors causes degeneration and death of neurons, which
may play a role in the delayed neuronal loss following cere-
bral ischemia and in the etiology of neurodegenerative disor-
ders [4] like epilepsy. It is also well known that glycine is an
obligatory co-agonist for NMDA receptor activation. There-
fore, the glycine site on NMDA receptors represents an inter-
esting target in the development of potential neuroprotective
drugs.
A number of compounds from different classes have been
recognized as functional antagonists at the glycine site. Sur-
veys on potential therapeutic uses of glycine site ligands and
on aspects of a structure–activity relationship were published
recently [5,6].
In recent papers the high affinity of pyrrolidine-2,3,4-
trione 3-oximes 1, dubbed PTOs [7], has been stated. Deriva-
* Corresponding author. Fax: +49-892-1807-7991.
E-mail address: hdsta@cup.uni-muenchen.de (H.-D. Stachel).
Fig. 1.
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.11.010

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H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
testing. These compounds may be seen as formal derivatives
of lactams 1 as well as regioisomers of compound 2.
which were obtained only as an inseparable mixture, along-
side the nitrone 10 as the main component. Accordingly,
N-methylation of the oxime 7 by diazomethane had occurred
rather than O-methylation. This mode of action of diaz-
omethane has been observed with other O-hydroxyimino-
carbonyl compounds [10].
2. Chemistry
The structure of the nitrone does not follow directly from
its spectra. In fact, the 1H NMR spectrum of compound 10 is
almost congruent with that of one of the isomeric oxime ethers
9. More conclusive information about the structure was
obtained from the combination of 1H and 13C NMR spectros-
copy used in the HMBC cross-coupling technique. From these
experiments it was concluded that the C-4 atom was con-
nected with another C atom across one heteroatom. The
sequence C–X–C was possible only when N-methylation of
oxime 7 had occurred to form nitrone 10. This structure was
finally confirmed by X-ray diffraction analysis (Fig. 4). It is
to be noted that we have obtained only the Z isomer, shown
in Fig. 3. The appearance of two more peaks of equal inten-
sity at 4.22 and 4.24 ppm in the 1H NMR spectrum of (Z)-10
after standing 1 week at room temperature probably indi-
cates slow equilibration with (E)-10 to a very small extent.
Compound 7 underwent nucleophilic displacement reac-
tions by heating with aliphatic or aromatic amines to give
We started from pyrrolone 4, which was prepared accord-
ing to literature [9]. The already reported 1H NMR spectrum
of this compound in chloroform as solvent gave evidence of
an equilibrium of two tautomers, depicted as A and B (R
= OMe) in Fig. 2, with the cyclic imino ester (B) as chief
component. In addition, traces of the enol form of this imino
ester must be present in the solution because compound 4
reacts with diazomethane slowly yielding the enol ether 6 in
low yield. Compound 6 has been obtained formerly by another
route [9].
A noticeable detail in the 1H NMR spectra of both com-
pounds 4B and 6 is the appearance of signals corresponding
to two hydrogens at a field much lower (8.1 ppm) than the
rest of the aromatic hydrogens. The deshielding effect on ortho
protons is apparently due to the neighboring polar C=N bond.
The split pattern of the phenyl signals proved to be a useful
means to ascertain the imino ester partial structure in the
derivatives of 4 described below.
By heating compound 4 with primary or secondary ali-
phatic amines the pyrrolones 5a–c were obtained. The IR
spectra of all compounds 5 showed the first bands in the
double bond region below 1650 cm–1 in accordance with the
ketene aminal structures, depicted asA (R = NR1R2) in Fig. 2.
1
The H NMR spectra indicated the existence of tautomers.
Taking 5a as an example, the solution in DMSO showed only
signals of the corresponding ketene aminal A (R = NHMe),
but, when dissolved in chloroform, alongside A the tauto-
meric cyclic amidine B (R = NHMe) was present in a ratio of
1:1. The latter compound was recognized by the characteris-
tic split pattern of the phenyl signals as mentioned above.
Compound 4 reacted rapidly with nitrous acid forming
oxime 7. The structure results from the spectra. As to be
expected for 7, the 13C NMR spectrum showed three signals
above 150 ppm and in the IR spectrum a carbonyl band
showed up at 1725 cm–1. Compound 7 reacted smoothly with
diazomethane to give a mixture of three new compounds. They
were identified as the O-methylated syn- and anti-oximes 9,
Fig. 3
.
Fig. 4
bility level.
. Molecular structure of 10 with thermal ellipsoids at the 50% proba-
Fig. 2
.

H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
393
oximes 8a–d. Compound 8a was also obtained by nitrosa-
tion of amidine 5b. All the compounds 8 resemble the parent
compound 7 with respect to their IR spectra. The carbonyl
bands showed up between 1725 and 1730 cm–1. However, in
contrast to the parent compound, the 1H NMR spectra revealed
the existence of the tautomeric nitroso 1H-pyrrolinone in chlo-
roform as solvent.
The reaction of oximes 8a–c with diazomethane yielded
only one compound each. The products were identified as
nitrones 11a–c by spectral evidence. The 1H NMR spectra of
all compounds 11 showed the characteristic split pattern of
the phenyl signals and N-Me singlets at 4.3 ppm. The carbo-
nyl bands in the IR spectra were found around 1700 cm–1and
in the mass spectra the typical [M – 16]+ peaks appeared
alongside the corresponding molecular ion peaks [11].
Compound 4 reacted quickly with nitric acid to give the
nitro compound 12, which was transferred into its derivatives
13a/b by heating with benzylamine or aniline, respectively.
In their IR spectra, all these compounds showed bands in the
double bond region below 1690 cm–1, and therefore, must be
formulated as nitropyrrolinones 12/13, respectively. This cor-
responds with the lack of split phenyl signals in the uniform
1H NMR spectra of compounds 12/13 when dissolved in
DMSO. Correspondingly it was to be expected that com-
pounds 12/13 would prove to be inert against diazomethane.
However, in ethereal solution the nitro compound 12 reacted
smoothly with this reagent to give an inseparable mixture of
two new compounds. They were identified as the geometri-
cal isomers of the methyl nitronate 14. Methyl esters of
nitronic acids are known to disproportionate upon heating to
give oximes and gaseous formaldehyde [11–14]. The ther-
molysis of the isomeric nitronates 14 was carried out at 150°
and gave formaldehyde and oxime 7. The methylation of nitro
compound 13a proceeded in the same way as described for
12 and gave the methyl nitronate 15 as a mixture of the geo-
metrical isomers. As expected, thermolysis of 15 yielded
oxime 8a. A remarkable feature of both nitronates 14/15 is
their stability with half-lives of certainly more than 1 year,
contrasting in that aspect most of the known nitronates [15].
Since some of the newly prepared substances proved active
in NMDA receptor binding tests, we were interested to pro-
duce analogs side-chain brominated compounds for compari-
son. For this purpose we needed compound 20a as starting
material. This compound was unknown and could not be
obtained by bromination of imino ester 4. It was described,
however, that the benzoyloxy-pyrrolone 16 can be bromi-
nated to yield pyrrolone 17 [16]. Either of the enol esters 16
and 17 reacted with trimethyloxonium tetrafluoroborate and
the methyl imidates 18 and 19a, respectively, were isolated
in moderate yield (Fig. 5). Not surprisingly, the analogs inter-
action of 17 with triethyloxonium tetrafluoroborate (Meer-
wein’s reagent) gave the ethyl imidate 19b. However, using
the same reagent in dimethoxyethane as solvent we obtained
the imidate 19a instead, apparently because of an intermedi-
ate transalkylation reaction between reagent and solvent. This
observation may be of interest because triethyloxonium tet-
rafluoroborate is the less expensive of the two reagents.
Fig. 5
.
Saponification of the benzoate 18 with weak alkali led to
imino ester 4. In comparison with the synthesis of 4 given in
literature, the new approach is more advantageous because
no methylation with diazomethane was needed. The analogs
saponification of benzoates 19a/b furnished the brominated
pyrrolones 20a/b. The IR and NMR spectra of 20a are quite
similar to those of the non-brominated analog 4 with the
exception, that no tautomerism was observed, neither in chlo-
roform nor in DMSO solution. In addition to the spectra, the
structure of compound 20b, including the Z-configuration,
was confirmed by X-ray diffraction analysis (Fig. 6). The sub-
stance crystallized as 1:1 adduct with benzene from the sol-
vent. For clarity, benzene was omitted in the drawing.
The amino compound 21 was formed by heating the pyr-
rolones 20a or 20b with benzylamine. Nitrosation of com-
pound 20a furnished oxime 22. Nitration of 20a gave the nitro
derivative 24. This compound reacted smoothly with diaz-
omethane to give the methyl nitronate 26. Thermolysis of 26
yielded the oxime 22. Both, the oxime 22 and the nitro com-
pound 24, reacted easily with amines producing the amino
substituted oximes 23a–c or the amino substituted nitro com-
pound 25a, b, respectively. The spectral characteristics of
compounds 21–26 are quite similar to those of the non-

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H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
On the other hand, oximes of the amidine type exhibited
distinct activity at the glycine site (8b: Ki = 9.2 µM, 23b:
Ki = 36 µM) despite the alleged essential NH group is lack-
ing. This, however, does not directly devaluate the pharma-
cophore model because the oximes we are dealing with are
prone to tautomerization to a high extent in polar solvents.
Therefore, the actual structures of the biologically active tau-
tomers are uncertain so that conclusions concerning structure–
activity relations cannot be drawn at this stage of the investi-
gation. It may be of interest to note that oxime 8b was more
potent at the glycine site than its structural isomer 28
(Ki = 72 µM) [8].
Distinctive receptor binding affinities were also observed
for the nitro compounds of the ketene N,O-acetal type (24:
Ki = 12.1 µM) as well as the aminal type (25b: Ki = 41 µM).
In these cases the non-brominated analogs are somewhat less
active (12: Ki = 71 µM or 13b: Ki ≥ 100 µM, respectively). It
may be noted that compound 12 was less potent at the gly-
cine site in comparison with its structural isomer 29
(Ki = 9 µM) [8] and that the nitrotetramic acid 27, formally
the parent compound of all brominated nitro compounds
described here, exhibited only medium high activity
(Ki = 60 µM). Due to their readiness to tautomerize, alike
their oxime analogs, the testing results of the nitro com-
pounds can presently be described only phenomenologically.
These initial findings encourage further investigation of
derivatives of lactam 27 and similar pyrroles in order to gain
insight into the structure–activity relationship, and to opti-
mize the glycine site activity.
Fig. 6. Molecular structure of 20b with thermal ellipsoids at the 50% proba-
bility level.
brominated analogs. However, because of the change in con-
figuration with respect to the phenyl substituent, the bromi-
nated imino esters and cyclic amidines showed no splitting
of the phenyl signals in the respective 1H NMR spectra.
Since compound 24 is formally derived from the hitherto
unknown tetramic acid 27, we have prepared this substance
by nitration of the side-chain brominated tetramic acid [16].
3. Pharmacological results and discussion
A selection of the new oximes and nitro compounds has
been tested for affinity to the glycine modulatory site associ-
ated with the NMDA receptor. The determination of the affini-
ties was carried out on pig cortical homogenates by measur-
ing the inhibition of [3H]MDL 105.519 binding [17] as
described in Section 4. Because of the poor water solubility
of the compounds 10 nM solutions in DMSO were used. The
final fraction of DMSO in the binding assays did not exceed
1%. The Ki values of the new compounds with reference to
glycine are given in Table 1.
4. Experimental protocols
No activity toward the receptor was observed with oximes
7 and 22, formally iminoesters of the active lactams 1a
(Ki = 19.4 µM) and 1b (Ki = 0.252 µM). This was to be
expected in the light of the glycine antagonist pharmacoph-
ore model proposed by Mawer et al. [19] in which an unsub-
stituted lactam (NH) group, putatively involved in hydrogen
bonding, was considered essential alongside an ionizable
group whose relative location is not critical.
4.1. General methods
Melting points (m.p.) were determined by using a Büchi
m.p. B-540 apparatus and are uncorrected. UV analysis was
performed in methanolic solution if not stated otherwise on
UV/VIS Spectrometer Lambda 20 (Perkin Elmer) or UV/VIS
Spectrophotometer Jasco V-530. Infrared spectra were mea-
sured as potassium bromide plates by using a FT-IR-
Spectrometer PARAGON 1000 (Perkin Elmer). 1H NMR spec-
tra (internal standard tetramethylsilane) were recorded on FT
NMR Spectrometer Elipse 400 (JEOL) or FT NMR Spectrom-
eter Elipse 500 (JEOL). The solvent was hexadeuteriodimeth-
ylsulfoxide if not indicated otherwise. Mass spectra were
recorded with a Hewlett Packard 5989A mass spectrometer
employing both EI (70 eV) and CI mode. MS-HR were obtained
with a JMS-GCMATE II (JEOL), MS-ESI with a API 2000
(Sciex) mass spectrometer. Microanalyses were carried out with
an CHN Analyzer Elementar Vario EL. CC: Flash column
250 ml (Baker) with silica gel 0.040–0.063 mm (Merck).
Table 1
Affinity toward glycine-binding site of the NMDA receptor channel
Compound
Glycine
1a
1b
8a
8b
8c
12
13b
23b
24
25b
27
Ki S.E.M. (µM)
0.200 0.040
19.4 1.9
0.252 0.033
56.9 9.8
9.22 1.27
15.9 2.0
71.0 8.2
≥100
36.3 5.2
12.1 4.5
41.2 0.9
60.7 5.9
72 [8]
4.2. NMDA receptor assay
[3H]MDL 105,519 binding to pig cortical brain mem-
branes was performed as previously described [17]. Test com-
28
29
9 [8]

H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
395
pounds insoluble in water were dissolved by addition of
DMSO. The total amount of DMSO in the assay did not
exceed 1% and inhibited binding only negligibly.
4.6. (Z)-2-Benzylidene-5-pyrrolidino-1,2-dihydropyrrol-3-
one (5c)
This compound was prepared from compound 4 (0.21 g,
1 mmol) and pyrrolidine (0.2 g, 3 mmol) analogously to the
synthesis of compound 5a. Light yellow crystals (acetoni-
trile), yield 0.20 g (83%). M.p. 213 °C. 1H NMR: d 8.56 (s,
1H), 7.58–7.26 (m, 5H), 6.25 (s, 1H), 4.50 (s, 1H), 3.63 (s,
2H), 3.38 (s, 2H), 1.94 (s, 4H); 13C NMR: d 181.3 (C-3),
166.2 (C-5), 135.3 (C-2), 129.6–127.6 (C-ar.), 106.6 (CH=),
82.2 (C-4), 49.6 (NCH2), 25.1 (CH2); IR: m 3383, 1628, 1577;
UV: kmax (log e) 227 nm (4.322), 330 (4.465); Anal. CHN
C15H16N2O (240.30). MS: 241 [M + 1]+.
IC50 values for test compounds were calculated from
experiments with at least six concentrations of test com-
pounds using Prism 2.0 (GraphPad Software, San Diego, CA).
The KD value for [3H]MDL 105,519 used in the Cheng–
Prusoff equation [18] to calculate Ki values was determined
in saturation experiments as 3.73 0.43 nM. If not stated
otherwise, data are expressed as mean S.E.M. of three
experiments, each carried out in triplicate.
4.3. (Z)-2-Benzylidene-5-methoxy-1,2-dihydropyrrol-3-one
(4)
4.7. (Z)-2-Benzylidene-3,5-dimethoxy-2H-pyrrole (6)
A solution of sodium methanolate (0.80 g, 15 mmol) in
methanol (10 ml) was added to a suspension of 1.5 g (5 mmol)
of compound 18 in methanol (10 ml). The clear solution
obtained within a few min was acidified with 1 N HCl (20 ml)
and extracted twice with ethyl acetate. The combined organic
layers were dried (Na2SO4) and evaporated in vacuo. The resi-
due crystallized from diisopropyl ether/ethanol 1:1. Yellow
crystals, yield 0.5 g (50%). M.p. 140 °C (lit. [9]: m.p. 139 °C).
Analytical and spectral data identical with data of [9].
13C NMR: d 184.3 (C-3), 178.6 (C-5), 133.8 (C-2), 129.6–
128.6 (C-ar.), 109.3 (CH=), 79.1 (C-4), 58.5 (MeO).
A solution of compound 4 (0.20 g, 1 mmol) in methanol
(10 ml) was treated with an excess of an ethereal solution of
diazomethane. After 6 h the volatile components were
removed and the residue purified by column chromatography
with petroleum ether as eluent. Yield 43 mg (20%). Analyti-
cal and spectral data identical with data of [9].
4.8. (Z)-2-Benzylidene-5-methoxy-2H-pyrrole-3,4-dione
4-oxime (7)
a:A solution of sodium nitrite (75 mg, 1.1 mmol) in 0.5 ml
water was added dropwise to a stirred ice-cooled suspension
of compound 4 (0.20 g, 1 mmol) in acetic acid (5 ml). After a
short time of stirring the product began to crystallize. The
precipitate was collected and washed several times with
diethyl ether/petroleum ether 1:1. Orange crystals, yield 0.19 g
(82%). M.p. 183 °C.
4.4. (Z)-2-Benzylidene-5-methylamino-1,2-dihydropyrrol-
3-one (5a)
A solution of compound 4 (0.10 g, 0.5 mmol) in methanol
(15 ml) was refluxed with an ethanolic solution of methy-
lamine (10 M, 1 ml, 10 mmol) for 15 min. The volatile com-
ponents were removed in vacuo and the residue was washed
several times with petroleum ether. Light yellow crystals
b: Compound 14 (26 mg, 0.1 mmol) was heated in diphe-
nyl ether (10 ml) to 150 °C for 5 min. The product was pre-
cipitated with petroleum ether. Yield 10 mg (43%).
1H NMR (geometrical isomers, ratio 3: 2): 8.12–8.18 (m,
2H), 7.32–7.51 (m, 3H), 6.74 (s, 0.6H), 6.68 (s, 0.4H), 4.12
1
(acetonitrile), yield 80 mg (80%). M.p. 209 °C. H NMR:
d 8.83 (s, 1H), 7.57–7.25 (m, 5H), 6.97 (s, 1H), 6.16 (s, 1H),
4.49 (s, 1H), 2.85 (s, broad, 3H); IR: m 3253, 1639, 1600,
1522 cm–1; UV: kmax (log e) 223 nm (4.285), 321 (4.442);
Anal. CHN C13H12N2O (200.24). MS: 201 [M + 1]+.
1H NMR (CDCl3, tautomer B): d 8.12 (d, 2H), 7.37–7.28
(m, 3H), 6.47 (s, 1H), 4.95 (br. s, 1H), 3.18 (d, 3H), 3.06 (s,
2H).
1
(s, 1.2H), 4.09 (s, 1.8H); H NMR (CDCl3): 8.12–8.06 (m,
2H), 7.48–7.37 (m, 3H), 6.93 (s, 1H), 4.22 (s, 3H); 13C NMR:
184.9 (C-3), 165.4/164.1 (C-5), 139.0 (C-2), 132.1–128.7
(C-4, C-ar.), 122.6 (CH=), 55.9 (OMe); IR: m 3176, 1725,
1631, 1559 cm–1; UV: kmax (log e) 304 nm (4.386), 316
(4.466), 331 (4.342); Anal. CHN C12H10N2O3 (230.23):
MS-EI: 230 [M+].
4.5. (Z)-5-Benzylamino-2-benzylidene-1,2-dihydropyrrol-3-
one (5b)
4.9. (Z)-5-Benzylamino-2-benzylidene-2H-pyrrole-3,4-
dione 4-oxime (8a)
A solution of compound 4 (0.21 g, 1 mmol) in methanol
(10 ml) was refluxed with 0.22 g benzylamine (2 mmol) for
15 min. The product separated on cooling. Light yellow crys-
a: To a suspension of compound 5b (0.14 g, 0.5 mmol) in
2 ml acetic acid was added under stirring an aqueous solution
of sodium nitrite (40 mg, 0.6 mmol). The product precipi-
tated within a few min. Yield 80 mg (52%). M.p. 165 °C.
b: A solution of compound 7 (0.14 g, 0.5 mmol) and ben-
zylamine (0.11 g, 1 mmol) in 15 ml methanol was refluxed
for 30 min. The mixture was diluted with water, acidified with
1
tals (MeOH), yield 0.20 g (72%). M.p. 233 °C. H NMR:
d 8.80 (s, 1H), 8.30 (s, 1H), 7.60–7.25 (m, 10H), 6.17 (s, 1H),
4.55 (br. s, 1H), 4.41 (br. s, 2H); IR: m 3335, 1632, 1597,
1498 cm–1; UV: kmax (log e) 222 nm (4.289), 322 (4.501);
Anal. CHN C18H16N2O (276.3). MS: 277 [M + 1]+.

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H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
1 N HCl (2 ml) and twice extracted with ethyl acetate. The
combined organic layers were dried (Na2SO4) and evapo-
rated. The residue crystallized from acetonitrile.Yield 50 mg
(33%).
c: This compound was prepared from 15 (33 mg, 0.1 mmol)
analogously to the synthesis of compound 7, method b.Yield
15 mg (50%).
(4.336). MS-HR Calc. for C17H12ClN3O2: 325.0618. Found
325.0612.
4.13. (Z)-2-Benzylidene-5-methoxy-2H-pyrrole-3,4-dione
4-(O-methyl-oxime) (9)
The mother liquor obtained in the preparation of 10 was
concentrated to half of the volume. The product (geometrical
isomers 1:1) separated on cooling. Yellow crystals, (20 mg,
17%). M.p. 143–145 °C. 1H NMR (geometrical isomers, ratio
1:1, CDCl3,): 8.15–8.05 (m, 2H), 7.48–7.32 (m, 3H), 6.85 (s,
0.5H), 6.91 (s, 0.5H), 4.32 (s, 1.5H), 4.30 (s, 1.5H), 4.22 (s,
1.5H), 4.18 (s, 1.5H); IR: m 2939, 1729, 1643, 1555 cm–1;
UV: kmax (log e) 316 nm (4.526), 331 (4.395); Anal. CHN
C13H12N2O3 (244.25). MS: 245 [M+1]+.
1H NMR (geometrical isomers, ratio 3:1): d 8.55 (br, 1H),
8.11–8.06 (m, 2H), 7.47–7.19 (m, 8H), 6.34 (s, 0.75H), 6.27
(s, 0.25H), 4.68 (d, 2H, J = 6 Hz); 1H NMR (CDCl3): 8.09 (s,
1H), 7.43–7.21 (m, 10H), 6.67 (s, 1H), 4.80 (br. s, 1H), 4.74
(d, 2H, J = 4.8 Hz); 13C NMR: 181.0 (C-3), 160.1/155.9 (C-5),
138.9/136.3 (C-2), 130.5–126.8 (C-4, C-ar.), 110.9/110.5
(CH=), 44.6 (N-CH2); IR: m 3385, 1726, 1664, 1638,
1576 cm–1; UV: kmax (log e) 258 nm (4.149), 327 (4.364),
340 (4.452), 356 (4.350); Anal. CHN C18H15N3O2 (305.24).
MS: 306 [M + 1]+.
4.14. (Z)-2-Benzylidene-5-methoxy-4-methylnitroryl-2,4-
dihydropyrrol-3-one (10)
A solution of compound 7 (0.11 g, (0.5 mmol) in metha-
nol was treated with an excess of an ethereal solution of dia-
zomethane. After the evolution of nitrogen had ceased the
solution was evaporated to dryness and the residue crystal-
lized from methanol (15 ml). (The mother liquor contains
compound 9). Red-brown crystals, yield 50 mg (41%). M.p.
4.10. (Z)-2-Benzylidene-5-phenylamino-2H-pyrrole-3,4-
dione 4-oxime (8b)
A solution of compound 7 (0.23 g, 1 mmol) and 0.30 g
(3 mmol) aniline in methanol (15 ml) was refluxed for 1 h.
The product separated on cooling. Reddish-brown crystals
1
1
(from MeOH), yield: 0.23 g (79%). M.p. 189 °C. H NMR
139 °C. H NMR (CDCl3): d 8.06 (dd, 2H), 7.45–7.35 (m,
(geometrical isomers, ratio 2:1): 9.66 (s, 0.3H), 9.53 (s, 0.7H),
8.14–8.08 (m, 2H), 7.45–6.95 (m, 8H), 6.57 (s, 0.7H), 6.49
(s, 0.3H); IR: m 3366, 1729, 1633, 1599, 1553 cm–1; UV: kmax
(log e) 249 nm (4.457), 354 (4.436), 369 (4.384); Anal. CHN
C17H13N3O2 (291.31). MS: 292 [M + 1]+.
3H), 6.90 (s, 1H), 4.33 (s, 3H, N-Me), 4.20 (s, 3H, O-Me);
13C NMR (CDCl3): d 181.2 (C-3), 165.9 (C-5), 140.1 (C-2),
134.1 (C-ar.), 132.3 (C-4), 130.5–128.6 (C-ar.), 121.0 (CH=),
55.8 (OMe), 53.5 (NMe). HMBC-experiment: coupling of
C(4) at 132.3 ppm and CH3-N at 4.33 ppm; IR: m 1703, 1635,
1552 cm–1; UV: kmax (log e) 318 nm (4.593), 326 (4.532),
345 (1.884); Anal. CHN C13H12N2O3 (244.25). MS-EI: 244
[M+]; 228 [M – 16]+.
4.11. (Z)-2-Benzylidene-5-(4-chloro-phenylamino)-2H-
pyrrole-3,4-dione 4-oxime (8c)
A solution of compound 7 (0.11 g, 0.5 mmol) and 0.25 g
(2 mmol) 4-chloroaniline (0.13 g, 1 mmol) was refluxed for
5 h in methanol (15 ml). The volatile components were
removed in vacuo and the residue was crystallized from etha-
nol. Reddish-brown powder, yield 70 mg (43%). M.p. 224 °C.
1H NMR (geometrical isomers, ratio 1:1): d 9.86 (s, 0.5H),
9.58 (s, 0.5H), 8.18–8.05 (m, 4H), 7.55–7.30 (m, 5H), 6.59
(s, 0.5H), 6.52 (s, 0.5H); IR: m 3399, 1719, 1626, 1593,
1556 cm–1; UV: kmax (log e) 259 nm (4.527), 354 (4.444),
370 (4.395); Anal. CHN C17H12ClN3O2 (325.75). MS:
326/328 [M + 1]+.
4.15. (Z)-5-Benzylamino-2-benzylidene-4-methylnitroryl-
2,4-dihydropyrrol-3-one (11a)
A solution of compound 8a (0.60 mg, 0.2 mmol) in metha-
nol (5 ml) was treated with an excess of an ethereal solution
of diazomethane. After the evolution of nitrogen had ceased
the solution was evaporated to dryness. Red-brown crystals
(diisopropyl ether/ethanol 1:1), yield 30 mg (47%). M.p.
1
165 °C (dec). H NMR (CDCl3): 8.12 (d, 2H, J = 7.5 Hz),
8.00 (br. s, 1H), 7.48–7.27 (m, 8H), 6.65 (s, 1H), 4.81 (d, 2H,
J = 5.6 Hz), 4.28 (s, 3H); 13C NMR (CDCl3): d 182.4 (C-3),
157.9 (C-5), 143.2 (C-2), 135.3–127.7 (C-ar.), 115.2 (CH=),
51.3 (OMe), 45.4 (NCH2); IR: m 3341, 1707, 1638, 1574,
1563 cm–1; UV: kmax (log e) 230 nm (4.191), 315 (4.497),
350 (4.420), 367 (4.353); Anal. CHN C19H17N3O2 (319.37).
MS-EI: 319 [M+]; 303 [M – 16]+.
4.12. (Z)-2-Benzylidene-5-(2-chloro-phenylamino)-2H-
pyrrole-3,4-dione 4-oxime (8d)
This compound was prepared from 7 (0.11 g, 0.5 mmol)
and 2-chloroaniline (0.13 g, 1 mmol) analogously to the syn-
thesis of compound 8c. Reddish-brown powder (from etha-
nol), yield 35 mg (21%). M.p. 187 °C. 1H NMR: d 10.13 (s,
1H), 8.88 (d, 1H, 8 Hz), 8.10 (d, 1H, 8 Hz), 7.65–7.19 (m,
7H), 6.63 (s, 1H); IR: m 3342, 1717, 1631, 1594, 1555 cm–1;
kmax (log e) 252 nm (4.376), 334 (4.330), 352 (4.374), 368
4.16. (Z)-2-Benzylidene-4-methylnitroryl-5-phenylamino-
2,4-dihydropyrrol-3-one (11b)
This compound was prepared from 8b (60 mg, 0.2 mmol)
with an excess of an ethereal solution of diazomethane analo-

H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
397
gously to the synthesis of compound 11a. Red-brown crys-
tals (MeOH), yield 25 mg (41%). M.p. 169 °C (dec). 1H NMR
(CDCl3): d 10.02 (s, 1H), 8.14 (d, 1H, 7.5 Hz), 7.90 (d, 1H,
7.5 Hz), 7.55–7.15 (m, 8 H), 6.79 (s, 1H), 4.34 (s, 3H); IR: m
3254, 1701, 1634, 1602, 1572, 1551 cm–1; UV: kmax (log e)
249 nm (4.234), 307 (4.283), 363 (4.278), 381 (4.257); Anal.
CHN C18H15N3O2 (305.34). MS-EI: 305 [M+], 289 [M – 16]+.
The product precipitated on cooling. Colorless crystals
(MeOH), yield 40 mg (66%). M.p. 264 °C. 1H NMR: d 10.83
(s, 1H), 10.45 (s, 1H), 7.65–7.30 (m, 10H), 6.67 (s, 1H); IR:
m 3194, 1694, 1619, 1585 cm–1; UV: kmax (log e) 325 nm
(4.533); Anal. CHN C17H13N3O3 (307.31). MS-ESI 308
[M + 1]+.
4.21. (Z)-2-Benzylidene-5-methoxy-4-methoxynitroryl-2,4-
dihydropyrrol-3-one (14)
4.17. (Z)-2-Benzylidene-4-methylnitroryl-5-(4-chloro-phe-
nylamino)-2,4-dihydropyrrol-3-one (11c)
A solution of compound 12 (50 mg, 0.2 mmol) in metha-
nol (5 ml) was treated with an excess of an ethereal solution
of diazomethane. After the evolution of nitrogen had ceased
the solution was evaporated to dryness and the residue crys-
tallized from diisopropyl ether/ethanol 1:1. Orange crystals,
yield 25 mg (48%). M.p. 176–178 °C. 1H NMR (geometrical
isomers, ratio 3:1): d 8.16–8.10 (m, 2H), 7.45–7.30 (m, 3H),
6.76/6.69 (2s, 1H), 4.15/4.13 (2s, 3H), 4.09/3.95 (2s, 3H);
13C NMR: d 181/177.9 (C-3), 165.0/164.9 (C-5), 140.3 (C-2),
134.1–128.5 (C-4, C-ar.), 118.2 (CH=), 55.8/55.6 (OMe),
54.8/54.6 (OMe); IR: m 1712, 1641, 1582, 1551 cm–1; UV:
kmax (log e) 316 nm (4.525); Anal. CHN C13H12N2O4
(260.25). MS: 261 [M + 1]+.
This compound was prepared from 8c (65 mg, 0.2 mmol)
with an excess of an ethereal solution of diazomethane analo-
gously to the synthesis of compound 11a. Red-brown crys-
tals (MeOH), yield 30 mg (44%). M.p. 187 °C. 1H NMR: d
10.21 (s, 1H), 8.12 (d, 1H, 8.5 Hz), 8.05 (d, 1H, 8.5 Hz),
7.58–7.35 (m, 7H), 6.67 (s, 1H), 4.26 (s, 3H); IR: m 3265,
1703, 1632, 1596, 1575, 1553 cm–1; UV: kmax (log e) 250 nm
(4.222), 306 (4.313), 363 (4.290), 382 (4.261). MS-HR Calc.
for C18H14ClN2O3: 339.0775. Found: 339.0787. MS-EI: 339
[M+]; 323 [M – 16]+.
4.18. (Z)-2-Benzylidene-5-methoxy-4-nitro-1,2-dihydropyr-
rol-3-one (12)
4.22. (Z)-5-Benzylamino-2-benzylidene-4-methoxynitroryl-
2,4-dihydropyrrol-3-one (15)
To a stirred ice-cooled suspension of compound 4 (0.20 g,
1 mmol) in acetic acid (3 ml) were added 0.5 ml of concen-
trated nitric acid. The product precipitated in good purity. Col-
orless crystals (MeOH), yield 0.10 g (40%). M.p. 186 °C. 1H
NMR: d 7.77–7.68 (m, 2H), 7.55–7.40 (m, 3H), 6.89 (s, 1H),
4.34 (s, 3H); 13C NMR: d 172.5 (C-3), 170.7 (C-5), 132.0
(C-2), 130.7–128.9 (ar.), 116.2 (CH=), 113.5 (C-4), 60.17
(OMe); IR: m 2681, 1690, 1633, 1590, 1460 cm–1; UV: kmax
(log e) 310 nm (4.403); Anal. CHN C12H10N2O4 (246.22).
MS: 247 [M + 1]+.
0.1 g (0.03 mmol) of compound 13a was treated with an
excess of an etheral solution of diazomethane. After the evo-
lution of nitrogen had ceased the solution was evaporated to
dryness and the residue crystallized from diisopropyl
ether/ethanol 1:1. Red-brown crystals, m.p. 134–136 °C,
yield: 50 mg (50%). 1H NMR (CDCl3): 8.11 (m, 2H), 7.46–
7.33 (m, 8H), 6.66 (s, 1H), 4.82 (d, 2H, J = 5.6 Hz), 4.04 (s,
3H); IR: m 3383, 1711, 1636, 1584 cm–1; UV: kmax (log e)
229 nm (4.205), 313 (4.388), 350 (4.407), 365 (4.3019. Anal.
CHN C19H17N3O3 (335.37). MS: 336 [M + 1]+.
4.19. (Z)-5-Benzylamino-2-benzylidene-4-nitro-1,2-dihy-
dropyrrol-3-one (13a)
4.23. Benzoic acid (Z)-2-benzylidene-5-methoxy-2H-
pyrrol-3-yl ester (18)
A solution of compound 12 (50 mg, 0.2 mmol) and ben-
zylamine (1.1 g, 10 mmol) in MeOH (15 ml) was refluxed for
15 min. The volatile components were removed in vacuo. The
residue crystallized from diisopropyl ether/ethanol 1:1. The
orange powder (benzylammonium salt of 13a, 55 mg) was
collected and dissolved in acetic acid (3 ml). Slowly the prod-
uct precipitated. Colorless powder (acetic acid), yield 35 mg
A stirred suspension of 16 [16] (2.9 g, 10 mmol) and 2.2 g
(15 mmol) trimethyloxonium tetrafluoroborate or 2.85 g
(15 mmol) triethyloxonium tetrafluoroborate in 1,2-
dimethoxyethane (30 ml) was heated to 65 °C for 30 min.
Passing through a period of clear solution the product slowly
precipitated. After completion of this process, the precipitate
was collected, dissolved in dichloromethane and the solution
washed with an aqueous solution of sodium carbonate (10%).
The organic layer was dried (Na2SO4), the volatile compo-
nents were removed in vacuo and the residue was crystal-
lized from MeOH. Faintly yellow crystals, yield 2.0 g (66%).
1
(53%). M.p. 213 °C. H NMR: d 10.26 (s, 1H), 9.90 (br. s,
1H), 7.60–7.28 (m, 10H), 6.60 (s, 1H), 4.88 (d, 2H, J = 6 Hz);
IR: m 3323, 1683, 1626, 1525 cm–1; UV: kmax (log e) 324 nm
(4.512); Anal. CHN C18H15N3O3 (321.34). MS: 322 [M +
1]+.
1
4.20. (Z)-2-Benzylidene-4-nitro-5-phenylamino-1,2-dihy-
dropyrrol-3-one (13b)
M.p 155 °C. H NMR (CDCl3): 8.25–8.15 (m, 4H), 7.68–
7.34 (m, 6H), 6.86 (s, 1H), 6.47 (s, 1H), 4.14 (s, 3H); IR: m
3464, 1747, 1644, 1589 cm–1; UV: kmax (log e) 235 nm
(4.363), 331 (4.424); Anal. CHN C19H15NO3 (305.34). MS:
306 [M + 1]+.
A solution of compound 12 (50 mg, 0.2 mmol) and aniline
(1.0 g, 10 mmol) in MeOH (15 ml) was refluxed for 15 min.

398
H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
4.24. Benzoic acid (Z)-2-(bromo-phenyl-methylene)-5-
methoxy-2H-pyrrol-3-yl ester (19a)
4.28. (Z)-5-Benzylamino-2-(bromo-phenyl-methylene)-1,2-
dihydropyrrol-3-one (21)
This compound was prepared from 17 [16] (1.85 g,
5 mmol) and 1.42 g (7.5 mmol) triethyloxonium tetrafluo-
roborate analogously to the synthesis of compound 18. Light
yellow crystals (diisopropyl ether/ethanol 1:1), yield 1.30 g
(68%). M.p. 119 °C. 1H NMR (CDCl3): d 7.52–7.05 (m, 10H),
6.63 (s, 1H), 4.14 (s, 3H); IR: m 1745, 1644, 1578 cm–1; UV:
kmax (log e) 240 nm (4.273), 290 (4.191), 304 (4.200); Anal.
CHN C19H14BrNO3 (384.23). MS: 384/386 [M + 1]+.
This compound was prepared from 20a (0.14 g, 0.5 mmol)
and benzylamine (0.22 g, 2 mmol) analogously to the
synthesis of compound 5b. Yellow crystals (MeOH), yield
0.12 g, (70%). M.p. 193 °C. 1H NMR: d 8.43 (s, 1H), 7.55 (s,
1H), 7.45–7.25 (m, 10H), 4.53 (s, 1H), 4.38 (br. s, 2H); IR: m
3256, 1630, 1581, 1507 cm–1; UV: kmax (log e) 307 nm
(4.373); Anal. CHN C18H15BrN2O (355.24). MS: 355/357
[M + 1]+.
4.25. Benzoic acid (Z)-2-(bromo-phenyl-methylene)-5-
ethoxy-2H-pyrrol-3-yl ester (19b)
4.29. (Z)-2-(Bromo-phenyl-methylene)-5-methoxy-2H-pyr-
role-3,4-dione 4-oxime (22)
A solution of compound 17 [16] (0.74 g, 2 mmol) and
0.66 g (3.5 mmol) triethyloxonium tetrafluoroborate in CHCl3
(30 ml) was refluxed for 3 h. The solution was washed with
an aqueous solution of sodium carbonate (10%). The organic
layer was dried (Na2SO4), the volatile components were
removed in vacuo and the residue was purified by column
chromatography with diethyl ether/petroleum ether (1:1) as
eluent. Faintly yellow crystals, yield 0.10 g (13%). M.p. 82 °C.
1H NMR (CDCl3): 7.55–7.17 (m, 10H), 6.61 (s, 1H), 4.55 (q,
2H), 1.45 (t, 3H); IR: m 2977, 1744, 1632, 1578; 1507 cm–1;
UV: kmax (log e) 241 nm (4.257), 289 (4.123), 305 (4.133);
Anal. CHN C20H16BrNO3 (398.30). MS: 398/400 [M + 1]+.
a. This compound was prepared from 20a (0.14 g, 0.5 mmol)
and sodium nitrite (40 mg, 0.6 mmol) analogsly to the syn-
thesis of compound 7. Light yellow crystals (acetic acid),
yield 0.85 mg (55%). M.p. 163 °C.
b. This compound was prepared from 26 (34 mg, 0.1 mmol)
analogously to the synthesis of compound 7 method b,
yield 15 mg (50%).
1H NMR (CDCl3): 7.48–7.37 (m, 5H), 4.21 (s, 3H);
1H NMR (geometrical isomers, ratio 1:2): 7.55–7.45 (m, 5H),
4.07 (s, 0.66H), 4.04 (s, 0.33H); IR: m 3448, 1729,
1625, 1565 cm–1; UV: kmax (log e) 264 nm (4.238), 291
(4.189); Anal. CHN C12H9BrN2O3 (309.12). MS: 309/311
[M + 1]+.
4.26. (Z)-2-(Bromo-phenl-methylene)-5-methoxy-1,2-dihy-
dropyrrol-3-one (20a)
4.30. (Z)-5-Benzylamino-2-(bromo-phenyl-methylene)-2H-
pyrrole-3,4-dione 4-oxime (23a)
This compound was prepared from 19a (1.15 g, 3 mmol)
and sodium methanolate (with 0.50 g, 9 mmol) in methanol
(10 ml) analogously to the synthesis of compound 4. Yellow
crystals (diethyl ether/petroleum ether 1:1), yield 0.63 g,
(75%). M.p. 119 °C. 1H NMR: d 9.65 (s, 1H), 7.45–7.30 (m,
A solution of compound 22 (62 mg, 0.2 mmol) and ben-
zylamine (0.11 g, 1 mmol) in 15 ml methanol was refluxed
for 30 min. The volatile components were removed in vacuo.
After washing twice with petrol ether the residue crystallized
upon addition of dichloromethane. Orange crystals, yield
1
5H), 4.77 (s, 1H), 3.93 (s, 3H); H NMR (CDCl3): d 7.60–
7.55 (m, 2H), 7.45–7.35 (m, 3H), 6.51 (br. s, 1H), 4.80 (d,
1H, J = 1.7 Hz); IR: m 3139, 1674, 1550 cm–1; UV: kmax (log
e) 288 nm (4.200), 364 (3.549); Anal. CHN C12H10BrNO2
(280.12). MS: 280/282 [M + 1]+.
1
35 mg (46%). M.p. 130 °C (dec). H NMR: d 8.50 (s, 1H),
7.52–7.25 (m, 10H), 5.74 (s, 1H), 4.64 (d, 2H, J = 5.6 Hz);
IR: m 34.18, 1731, 1669, 1616, 1560 cm–1; UV: kmax (log e)
258 nm (4.176), 321 (4.283). MS-HR Calc. for C18H14BrN3O2
383.0269. Found: 383.0227.
4.27. (Z)-2-(Bromo-phenl-methylene)-5-ethoxy-1,2-dihy-
dropyrrol-3-one (20b)
4.31. (Z)-2-(Bromo-phenyl-methylene)-5-phenylamino-2H-
pyrrole-3,4-dione 4-oxime (23b)
This compound was prepared from 19b (0.39 g, 1 mmol)
and sodium methanolate (0.36 g, 3 mmol) in methanol (10 ml)
analogously to the synthesis of compound 4. Yellow crystals
(benzene/diethyl ether 1:1). 20b crystallized as 1:1 adduct
with benzene; The analytical data were taken after heating
the crystals to 120 °C for 20 min in vacuo.Yield 0.14 g (47%).
M.p. 144 °C. 1H NMR: 9.62 (s, 1H), 7.45–7.27 (m, 5H), 4.77
(s, 1H), 4.22 (q, 2H), 1.35 (t, 3H). IR: m 3085, 1678,
1548 cm–1; kmax (log e) 288 nm (4.260), 364 (3.532); Anal.
CHN C13H12BrNO2 (294.15). MS: 294/296 [M + 1]+.
A solution of compound 22 (62 mg, 0.2 mmol) and 0.1 g
(1 mmol) aniline in methanol (15 ml) was refluxed for 15 min.
The product crystallized on cooling. Red-brown crystals,
yield: 35 mg (47%). M.p. 127 °C (dec). 1H NMR: d 9.64 (s,
1H), 9.50 (s, 1H), 8.15/8.06 (2d, 2H, J = 7.7 Hz), 7.51–7.31
(m, 7H), 7.18–7.12 (m, 1H); IR: m 3398, 1727, 1622,
1561 cm–1; UV: kmax (log e) 338 nm (4.352). MS-HR Calc.
for C17H12BrN3O2 352.9987. Found: 352.9955.

H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
399
4.32. (Z)-2-(Bromo-phenyl-methylene)-5-(4-chloro-phenyl-
amino)-2H-pyrrole-3,4-dione 4-oxime (23c)
3H), 3.96 (s, 1H), 3.93 (s, 2H); IR: m 1720, 1627, 1586,
1547 cm–1; UV: kmax (log e) 303 nm (4.431); Anal. CHN
C13H11BrN2O4 (339.15). MS: 339/341 [M + 1]+.
This compound was prepared from 22 (62 mg, 0.2 mmol)
and 40 mg (0.3 mmol) 4-chloroaniline analogously to the syn-
thesis of compound 23b. Red-brown crystals (MeOH), yield:
35 mg (43%). M.p. 146 °C. 1H NMR: d 9.85 (s, 1H), 9.52 (s,
1H), 8.25–8.05 (m, 2H), 7.55–7.30 (m, 7H); IR: m 3402, 1727,
1615, 1557 cm–1; UV: kmax (log e) 242 nm (4.413), 344
(4.401);Anal. CHN C17H11BrClN3O2 (404.65). MS: 405/407
[M + 1]+.
4.37. (Z)-2-(Bromo-phenyl-methylene)-3-hydroxy-4-nitro-
1H-pyrrol-5-one (27)
This compound was prepared from 0.28 g (1 mmol) (Z)-
2(Bromo-phenyl-methylene)-3-hydroxy-1H-pyrrol-5-one
[16] and nitric acid analogously to the synthesis of com-
pound 12. Light yellow crystals (MeOH), yield 0.17 g (52%).
1
M.p. 112–114 °C. H NMR: d 8.77 (s, 1H), 7.40–7.22 (m,
5H); IR: m 3166, 3063, 1726, 1600 cm–1; UV: kmax (log e)
254 nm (4.041), 316 (4.282); Anal. CHN C11H7BrN2O4
(311.09).
4.33. (Z)-2-(Bromo-phenyl-methylene)-5-methoxy-4-nitro-
1,2-dihydropyrrol-3-one (24)
This compound was prepared from 20a (0.14 g, 0.5 mmol)
and nitric acid analogously to the synthesis of compound 12.
Colorless crystals (MeOH), yield 0.11 g (68%). M.p. 199 °C.
1H NMR: d 7.49–7.35 (m, 5H), 4.36 (s, 3H); IR: m 3115, 1692,
1597 cm–1; UV: kmax (log e) 309 nm (4.329); Anal. CHN
C12H9BrN2O4 (325.12). MS: 325/327 [M+ + 1].
4.38. X-ray diffraction analysis of 10 and 20b
Diffraction data were collected with MoKa radiation
(k = 0.71073 Å, graphite monochromator) on a Nonius Kap-
paCCD. Crystal data are given in Table 2. The structures were
Table 2
Summary of crystal data for compounds 10 and 20b
4.34. (Z)-5-Benzylamino-2-(bromo-phenyl-methylene)-4-
nitro-1,2-dihydropyrrol-3-one (25a)
10
13H12N2O3
244.246
20b
Formula
Mr (g mol–1
C
C16H15BrNO2
)
333.200
Monoclinic
P21/c
A solution of compound 24 (65 mg, 0.2 mmol) and ben-
zylamine (1.1 g, 10 mmol) in MeOH (15 ml) was refluxed for
1 h. The volatile components were evaporated. The residue
was washed twice with petroleum ether and recrystallized
from diisopropyl ether/ethanol 1:1. Faintly yellow crystals,
Crystal system
Space group
a (Å)
Triclinic
P-1
4.5344(2)
11.4755(5)
11.9738(7)
73.3569(16)
82.5614(17)
80.022(2)
585.81(5)
2
7.8138(2)
16.8341(3)
11.1207(2)
90
b (Å)
c (Å)
1
yield 25 mg (31%). M.p. 203 °C. H NMR: d 9.90 (s, 1H),
␣ (°)
7.51–7.25 (m, 11H), 4.96 (d, 2H, J = 4.9 Hz); IR: m 3347,
1688, 1658, 1524 cm–1; UV: kmax (log e) 284 nm (4.324),
316 (4.411). MS-HR Calc. for C18H14BrN3O3 399.0219.
Found: 399.0221.
b (°)
102.1691(10)
90
c (°)
V (Å3)
Z
1429.93(5)
4
q (g cm−3
µ (mm−1
)
1.38470(12)
0.100
1.54777(5)
2.875
)
4.35. (Z)-2-(Bromo-phenyl-methylene)-5-phenylamino-4-
nitro-1,2-dihydropyrrol-3-one (25b)
Crystal size (mm)
Temperature (K)
h-range (°)
0.20 × 0.12 × 0.04 0.26 × 0.05 × 0.03
200(2)
3.55–24.98
3231
200(2)
3.16–27.50
9634
This compound was prepared from 24 (65 mg, 0.2 mmol)
and aniline (1.0 g, 10 mmol) in MeOH (15 ml) analogously
to the synthesis of compound 25a. Light yellow powder (diiso-
propyl ether/ethanol 1:1), yield 50 mg (64%). M.p. 202 °C.
1H NMR: d 10.87 (s, 1H), 9.64 (s, 1H), 7.65–7.32 (m, 10H);
IR: m 3271, 3063, 1691, 1628, 1590 cm–1; UV: kmax (log e)
315 nm (4.498); Anal. CHN C17H12BrN3O3 (386.21). MS:
386/388 [M + 1]+.
Reflections for metrics
Absorption correction
Transmission min/max
Reflections collected
Independent reflections
Rint
no
Numerical
0.6054–0.9295
30033
–
6037
2050
3273
0.0458
0.0587
0.0978
0.0635
2140
r(I)/I
Observed reflections (I ≥ 2r(I)) 1492
x, y (weighting scheme)
Extinction
0.0637, 0
0.0453, 0.0471
0.0116(11)
242
–
4.36. (Z)-2-(Bromo-phenyl-methylene)-5-methoxy-4-meth-
ylnitroryl-2,4-dihydropyrrol-3-one (26)
Parameters refined
Restraints
211
0
0
R(Fobs
)
0.0437
0.0419
0.0962
1.040
Rw(F2)
0.1154
1.025
0.001
0.233
This compound was prepared from 24 (65 mg, 0.2 mmol)
and excessive diazomethane analogously to the synthesis of
compound 14. Orange crystals (diisopropyl ether/ethanol 1:1),
yield 40 mg (59%). M.p. 126–128 °C. 1H NMR (CDCl3, geo-
metrical isomers, ratio 1:1): d 7.48–7.35 (m, 5H), 4.21 (s,
S
Shift/errormax
0.001
Largest diff. peak (e Å−3
)
0.609
Largest diff. hole (e Å−3
)
−0.193
−0.515

400
H. Poschenrieder et al. / European Journal of Medicinal Chemistry 40 (2005) 391–400
[9] H.-D. Stachel, H. Poschenrieder, E. Immerz-Winkler, J. Heterocycl.
Chem. 20 (1983) 935–941.
solved with SIR97 [20] and refined using full-matrix least
squares on F2 with SHELXL-97 [21]. The drawings
(Figs. 4 and 6 were generated with ORTEP [22]. Further
details are available under the depository numbers CCDC
243280 (10) and CCDC 243281 (20b) from the Cambridge
Crystallographic Data Center, 12, Union Road Cambridge
CB2 1EZ, UK (Fax: +44-1233-336-033; email:
deposit@ccdc.cam.ac.uk).
[10] B. Eistert, R. Müller, H. Selzer, E.-A. Hackmann, Ber. Dtsch. Chem.
Ges. 97 (1964) 2469–2478.
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1989, pp. 139ff.
[12] J.U. Nef, Liebigs Ann. Chem. 280 (1894) 263–291.
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