Synthesis of new iminocoumarins and their transformations into N-chloro and hydrazono compounds

Article abstract of DOI:10.1016/j.tet.2005.05.020

The Knoevenagel reaction between 2-hydroxybenzaldehydes and active methylene compounds (malononitrile and ethyl cyanoacetate) produces iminocoumarins and/or coumarins. In order to study the reactivity of the prepared iminocoumarins, chlorination and reaction with N-nucleophiles were studied.

Full text of DOI:10.1016/j.tet.2005.05.020

Tetrahedron 61 (2005) 7012–7021
Synthesis of new iminocoumarins and their transformations into
N-chloro and hydrazono compounds
Julija Volmajer,a Renata Toplak,a,† Ivan Lebanb and Alenka Majcen Le Marechala,
*
aFaculty of Mechanical Engineering, University of Maribor, Smetanova 17, 2000 Maribor, Slovenia
ˇ ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
b
Received 20 January 2005; revised 18 April 2005; accepted 5 May 2005
Abstract—The Knoevenagel reaction between 2-hydroxybenzaldehydes and active methylene compounds (malononitrile and ethyl
cyanoacetate) produces iminocoumarins and/or coumarins. In order to study the reactivity of the prepared iminocoumarins, chlorination and
reaction with N-nucleophiles were studied.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
nitriles) were prepared using Knoevenagel condensation
procedures, in one-pot reactions from 2-hydroxy-
benzaldehyde derivatives 1a–g and malononitrile 2 in the
presence of catalytic amounts of piperidine. The spon-
taneous cyclisation between the ortho hydroxy group and
the side-chain cyano group of intermediate 3 led to
iminocoumarin derivatives in moderate to good yields
(47–98%), (Scheme 1).
Natural and synthetic coumarin derivatives represent,
nowadays, an important group of organic compounds that
are used as antibiotics,1,2 fungicides,3 anti-inflammatory,4
anticoagulant5 and antitumor agents.6,7 Regarding their high
fluorescence ability, they are widely used as optical
whitening agents, brighteners, laser dyes and also as
fluorescent probes8 in biology and medicine.9 Their
2-imino analogues, iminocoumarins, are less known and
comprise a very important class of protein tyrosine kinase
(PTK) inhibitors with low molecular weight.10,11 A great
number of PTK inhibitors have been introduced recently as
potential anti cancer agents. Some of them which derive
from different 2-hydroxybenzaldehydes and cyanoaceta-
mides, display moderate antitumour activity against P.388
lymphocytic leukaemia.12 In order to obtain a larger
spectrum of biologically active iminocoumarin substances,
a novel series has been developed which contain the
2-iminocoumarin unit. In this paper we are expanding our
preliminary results13 to new differently substituted imino-
coumarins, and to their possible chemical and biological
activities.
In contrast, reactions of the 2-hydroxybenzaldehydes 1b–g
with ethyl cyanoacetate 5 do not lead just to iminocoumarins
8, but also to coumarins 9, 10. The formation of
iminocoumarins 8 and/or coumarins 9, resulting from
Knoevenagel condensation between the 2-hydroxybenzal-
dehydes 1 and ethyl cyanoacetate 5 was followed by an
attack of the hydroxyl group of the intermediate (6 or 7) on
the side-chain nitrile or ester group. The ratio between the
products depends on the nature of the aromatic ring
substituents (Scheme 2).
The Knoevenagel reaction between ethyl cyanoacetate 5
and 2-hydroxybenzaldehyde containing another hydroxyl
group (1b, 1c, 1d) on the aromatic ring, forms imino-
coumarins with only minor quantities of coumarins 9. This
suggests that the condensation in these cases is stereo-
selective yielding E-styryl derivatives 6 as the main
intermediates in which the aromatic ring and the cyano
group are in the cis configuration.
2. Results and discussion
Iminocoumarins 4a–g (2-imino-2H-chromene-3-carbo-
Keywords: Knoevenagel condensation; Iminocoumarins; Coumarins; N-
Chlorination; N-Chloro iminocoumarins; N-Hydrazonocumarins.
The coumarins 9 were formed as the main products, when
the Knoevenagel reactions were performed between
2-hydroxy-4-methoxybenzaldehyde 1e, or 4-diethylamino-
2-hydroxybenzaldehyde 1g and ethyl cyanoacetate 5.
*
Corresponding author. Tel.: C386 2 220 7910; fax: C386 2 220 7990;
e-mail: alenka.majcen@uni-mb.si
ˇ
Present address: Lek d.d., Verovskova 57, 1526 Ljubljana, Slovenia.
†
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.020

J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
7013
Scheme 1. Reaction conditions: (i) piperidine, EtOH, rt.
Scheme 2. Reaction conditions: (i) piperidine, EtOH, rt.

7014
J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
Table 1. Iminocoumarins and coumarins
The formation of iminocoumarins and/or coumarins arises
from the E/Z isomerisations of the styryl intermediate. We
did not study which factors control the different selectivity
to styryl intermediate 6 and/or 7 (Scheme 2), but it is evident
that the effect of the substituents on the aromatic ring plays
an important role. For example, salicylaldehyde derivatives
containing groups with more negative inductive effect (Br,
OH) yield in the Knoevenagel reaction, the E-styryl
intermediate as the main intermediate. Furthermore, the
results also indicate the involvement of an additional OH
group on the phenyl ring in the stabilization of the E-styryl
intermediate, supposedly through the formation of inter-
molecular hydrogen bonds.
Compound
Y
Yield (%)
Mp (8C)
8a13
8b13
8c
6-OH
8-OH
7-OH
6-OH
8-OH
7-NEt2
7-OCH3
7-OCH3
6-Br
70
84
91
17
1
89
85
3
240–242
225–226
220–221
237–238
228–230
211–212
225–226
132–133
180–181
9a13
9b13
9d
9e
10e
10f
44
Iminocoumarins were also formed in minor quantites but we
succeeded in isolating only the product of their hydrolysis,
coumarins 10. For example, in the reaction between the
5-bromo-2-hydroxybenzaldehyde 1f and ethyl cyanoacetate
5 only the hydrolysed iminocumarin 10f was isolated
(Scheme 2, Table 1).
The formation of coumarin and chromene derivatives
during the Knoevenagel reaction is known,14 as well as
the transformations15 of iminocoumarins into coumarins in
basic aprotic solvents. The isomerisation of the 2-imino-2H-
1
chromene-3-carboxamide was studied by H NMR.16 In a
The structure of the iminocoumarin and coumarin deriva-
tives was determined by IR, H NMR, mass spectra and
DMSO-d6 solution of 2-imino-2H-chromene-3-carboxa-
mide, a mixture of 2-imino-2H-chromene-3-carboxamide
and its isomer 2-cyano-3-(2-hydroxyphenyl)-prop-2-
enamide was observed. The authors explain the result as a
consequence of the pyran ring opening.
1
elemental analysis. We can distinguish between coumarin
and iminocoumarin formations on the basis of the IR
spectra. Namely, the NH absorption band of the imino group
observed between 3278 and 3312 cmK1 (KBr) indicates the
formation of iminocoumarins.
We focused our attention firstly on an investigation of the
Scheme 3.

J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
7015
11f (Scheme 3). The average to low yields of N-chlorination
indicates a polymerisation ability for the prepared N-chloro
derivatives. The structures of the chloro iminochromenes
1
were determined by IR, H NMR, 13C NMR, mass spectra
and elemental analysis. The structures of the chloro
iminochromene 11b13 and dimeric compound 13 were
additionally confirmed by X-ray diffraction (Figs. 1 and 2)
(Table 2).
The reactions of 2-iminochromene-3-carboxamides with
N-phenylhydrazine17 or primary amines18 in acetic acid at rt
are known and lead to 2-N-substituted imincoumarins only.
Figure 1. ORTEP view of the compound 11b. Crystallographic data for the
structure 11b have been deposited within the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 200890.
When we carried out a reaction between the 6-hydroxy-2-
imino-2H-chromene-3-carbonitrile 4b and N-phenylhydra-
zine 14a in an acetic acid medium according to the above
mentioned method, the reaction led to two products
6-hydroxy-2-(phenylhydrazono)-2H-chromene-3-carbo-
nitrile 15b and 2,5-dihydroxybenzaldehyde phenylhydra-
zone 18 (Scheme 3). Phenylhydrazine as N-nucleophile in
this case attacked the C2 and C4 electrophilic centres. The
selective formation of N-hydrazonochromenes proceeded in
the reactions of 2-iminocoumarin-3-carbonitriles with
hydrazine derivatives (phenylhydrazine 14a, 2-hydrazino-
pyridine 14b, N-phenylhydrazinecarboxamide 14c)
(Scheme 3) in glacial acetic acid at rt in the presence of
NH4OAc or NaOAc. In this case the reactions took place
without iminolactone ring opening.
The structures of compounds N-hydrazonochromenes were
1
assigned by IR, H NMR, 13C NMR, mass spectra and
elemental analysis. The structure of the products 15f and
17e were confirmed by X-ray diffraction (Figs. 3 and 4)
(Table 3).
Figure 2. ORTEP view of the compound 13. Crystallographic data for the
structure 13 have been deposited within the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 260165.
The antibacterial activity of the iminocoumarins and
their derivatives was evaluated against common Gram-
positive bacteria and Gram-negative bacteria. The chloro-
iminochromenes exhibit excellent antibacterial activity.
Iminochromenes showed moderate activity whereas
N-hydrazonochromenes did not exhibit antibacterial activity
iminocoumarins chlorination with sodium hypochlorite.
The chlorination of the imino group of iminocoumarins with
sodium hypochlorite yields chloroimino chromenes 11a–g.
The reactions were performed under acidic reaction
conditions at 0 8C (Scheme 3). Within a few minutes the
reaction was complete and the products precipitated from
the reaction mixture on the addition of cold water.13
The N-chlorination of 6-hydroxy-2-imino-2H-chromene-3-
carbonitrile 4b and 6-hydroxy-2-imino-2H-chromene-3-
carboxylate 8a were accompanied by an electrophilic
aromatic chlorination yielding compound 12b and 12g. In
the reaction between 6-bromo-2-imino-2H-chromene-3-
carbonitrile 4f and sodium hypochlorite, dimeric product
13 was isolated beside the expected chloroimino chromene
Table 2. N-Chloroiminochromenes
Compound
Y
X
Yield (%)
Mp (8C)
11a13
11b13
11c
11d
11e
H
CN
CN
CN
CN
CN
CN
COOEt
CN
COOEt
40
41
48
52
41
30
26
11
13
191–192
209–210
210–211
210–211
224–225
200–201
176–177
204–205
152–153
6-OH
7-OH
8-OH
7-OCH3
6-Br
6-OH
6-OH
6-OH
11f
11g13
12b13
12g13
Figure 3. ORTEP view of the compound 15f. Crystallographic data for the
structure 15f have been deposited within the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 260163.

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J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
9e, 10e, 10f were isolated. We noticed that the ratio between
the possible products depends on the nature of the aromatic
ring substituents. A series of new N-chloro iminocoumarin
11a–g was prepared in moderate yields, by reacting sodium
hypochlorite in an acidic medium with iminocoumarins.
The reaction of the iminocoumarins with hydrazines led to
N-hydrazonochromenes 15a–f, 16a–d, 17a–e.
4. Experimental
Melting points were determined with Kofler hot stage
apparatus. 1H NMR spectra were recorded on a Bruker
Avance DPX 300 (300 MHz) spectrometer with DMSO-d6
as solvents and TMS as internal standard. 13C NMR spectra
were obtained on a Bruker AM 300 spectrometer at 75 MHz
with DMSO-d6 as solvents and TMS as internal standard.
Mass spectra were performed on an Autospec Q spec-
trometer. The microanalyses for C, H and N were obtained
on a Perkin-Elmer Analyser 2400. IR spectra were
determined with a Perkin-Elmer 225 or a 1420 spec-
trometer. Column chromatography (CC) was performed on
silica gel (Fluka, silica gel 60, 0.035–0.070 mm). All
starting materials were commercially available (in most
cases from Fluka).
Figure 4. ORTEP view of the compound 17e. Crystallographic data for the
structure 17e have been deposited within the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 260164.
Table 3. N-Hydrazonochromenes
Compound
Y
X
Yield (%)
Mp (8C)
15a
15b
15c
15d
15e
15f
16a
16b
16c
16d
17a
17b
17c
17d
17e
H
6-OH
8-OH
7-OCH3
6-OH
8-OH
H
6-OH
8-OH
8-OH
H
CN
CN
CN
CN
COOEt
COOEt
CN
CN
CN
COOEt
CN
CN
CN
COOEt
COOEt
37
41
38
47
31
64
48
40
38
49
51
68
53
87
91
205–206
258–259
O260
247–248
178–179
208–209
164–165
246–247
255–256
146–147
O260
O260
O260
231–232
226–227
4.1. General procedure for Knoevenagel reactions
between 2-hydroxybenzaldehyde derivatives and
malononitrile
A mixture of substituted 2-hydroxybenzaldehyde 1
(5 mmol) and malononitrile 2 (5 mmol) was dissolved in
5 mL of ethanol and one drop of piperidine was added. The
reaction mixture was stirred at rt for 30 min. The product
was precipitated from the reaction mixture and collected by
filtration. It was recrystallized from an appropriate solvent.
6-OH
8-OH
6-OH
8-OH
The following compounds were prepared in this manner.
at all. The preliminary studies of antiproliferative activity
for compound 11b on MCF-7 cells in vitro are promising.
The survival of MCF-7 tumor cells cultured in a medium
with compound 11b drops beyond 40% at a concentration of
11b above 112.5 mM.
4.1.1. 2-Imino-2H-chromene-3-carbonitrile 4a. Prepared
from salicylaldehyde 1a (610 mg, 5 mmol) and malono-
nitrile 2 (330 mg, 5 mmol) in 61% (518 mg) yield as a white
solid; mp 140–141 8C; (mp19 183–185 8C) (EtOH). EI-MS:
1
m/zZ170 (MC). H NMR (DMSO-d6): 7.18–7.21 (1H, m,
The synthesised iminocoumarins with electron donor
groups at 6-position (4b, 8a) and at 7-position (4c, 4e, 4g)
revealed a high fluorescence efficiency while other imino-
coumarins were photophysically inert.
H8); 7.24–7.29 (1H, m, H6); 7.55–7.61 (2H, m, H5, H7); 8.37
(1H, d, JZ0.9 Hz, H4); 8.83 (1H, s NH). (Found: C, 70.31;
H, 3.60, N, 16.37. C10H6N2O requires: C, 70.58; H, 3.55; N,
16.46); nmax (KBr) 3293, 2231, 1653 cmK1
.
It is interesting to note that some iminocoumarins undergo a
dramatic change of colour with any change of pH in the
medium. For example, iminocoumarins 4b, 4d, 8a, 8b
exhibit a green colour in the acidic medium but they change
to a red colour in the basic medium.
4.1.2. 6-Hydroxy-2-imino-2H-chromene-3-carbonitrile
4b. Prepared from 2,5-dihydroxybenzaldehyde 1b
(690 mg, 5 mmol) and malononitrile 2 (330 mg, 5 mmol)
in 98% (912 mg) yield as a yellow-green solid; mpO260 8C
1
(EtOH). EI-MS: m/zZ186 (MC). H NMR (DMSO-d6):
6.39–7.04 (3H, m, H5, H7, H8); 8.31 (1H, s, H4); 8.61 (1H, s,
NH); 9.75 (1H, br s, OH). 13C NMR (DMSO-d6): d 104.1,
113.7, 115.2, 116.3, 117.5, 121.4, 146.8, 146.9, 152.0,
153.4. (Found: C, 64.38; H, 3.19; N, 15.39. C10H6N2O2
requires: C, 64.52; H, 3.25; N, 15.05); nmax (KBr) 3242,
3. Conclusion
According to our results, we can conclude that imino-
coumarins 4a–g, 8a–c were formed in condensation
between salicylaldehyde derivatives and malononitrile,
and in the reaction of ethyl cyanoacetate and hydroxy
substituted salicylaldehydes. In other cases, coumarins 9d,
2236, 1652 cmK1
.
4.1.3. 7-Hydroxy-2-imino-2H-chromene-3-carbonitrile
4c. Prepared from 2,4-dihydroxybenzaldehyde 1c

J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
7017
(690 mg, 5 mmol) and malononitrile 2 (330 mg, 5 mmol) in
90% (837 mg) yield as a yellow solid; mpO260 8C (EtOH).
EI-MS: m/zZ186 (MC). 1H NMR (DMSO-d6): 6.51 (1H, d,
JZ2.0 Hz, H8); 6.65–6.68 (1H, m, H6); 7.40 (1H, d, JZ
8.7 Hz, H5); 8.20 (1H, s, H4); 8.65 (s, 1H, NH). EI-HRMS:
m/zZ186.0435 (MC); C10H6N2O2 requires: 186.0429
4.2.1. Ethyl 6-hydroxy-2-imino-2H-chromene-3-car-
boxylate 8a and 6-hydroxy-2-oxo-2H-chromene-3-
carbonitrile 9a. Prepared from 2,5-dihydroxybenzaldehyde
1b (690 mg, 5 mmol) and ethyl cyanoacetate 5 (0.55 mL,
5 mmol). Compound 8a was precipitated from the reaction
mixture in 70% (815 mg) yield as a yellow-green solid; mp
240–242 8C (EtOH). EI-MS: m/zZ233 (MC). 1H NMR
(DMSO-d6): 1.32 (3H, t, JZ7.2 Hz, CH2CH3); 4.34 (2H, q,
JZ7.2 Hz, CH2CH3); 7.01 (3H, m, H5, H7, H8); 8.25 (1H, s,
H4); 9.25 (1H, s, NH); 9.63 (1H, br s, OH). (Found: C,
61.88; H, 4.49; N, 5.83. C12H11NO4 requires: C, 61.80; H,
(MC); nmax (KBr) 3259, 2222, 1658 cmK1
.
4.1.4. 8-Hydroxy-2-imino-2H-chromene-3-carbonitrile
4d. Prepared from 2,3-dihydroxybenzaldehyde 1d
(690 mg, 5 mmol) and malononitrile 2 (330 mg, 5 mmol)
in 47% (438 mg) yield as a yellow-green solid; mpO260 8C
4.75; N, 6.01); nmax (KBr) 3282, 1726, 1633 cmK1
.
1
(EtOH). EI-MS: m/zZ186 (MC). H NMR (DMSO-d6):
Compound 9a was isolated using column chromatography
(ethyl acetate) on the residue from the evaporated residue. It
was isolated in 15% (140 mg) yield as a yellow solid; mp
237–238 8C (EtOH); (mp20 273–238.5 8C). EI-MS: m/zZ
7.98–7.01 (1H, m, H7); 7.03–7.06 (1H, m, H6); 7.8–7.10
(1H, m, H5); 8.31 (1H, s, H4), 8.65 (1H, s, NH). (Found: C,
64.73; H, 3.38; N, 14.85. C10H6N2O2 requires: C, 64.52; H,
187 (MC). 1H NMR (DMSO-d6): 7.11 (1H, d, JH6H4
Z
3.25; N, 15.05); nmax (KBr) 3344, 2225, 1646 cmK1
.
3.0 Hz, H5); 7.21 (1H, dd, JH4H3Z9.0 Hz, JH4H6Z3.0 Hz,
H7); 7.36 (1H, d, JH3H4Z9.0 Hz, H8); 8.87 (1H, s, H4);
4.1.5. 7-Methoxy-2-imino-2H-chromene-3-carbonitrile
4e. Prepared from 2-hydroxy-4-methoxybenzaldehyde 1e
(760 mg, 5 mmol) and malononitrile 2 (330 mg, 5 mmol) in
58% (580 mg) yield of a white solid; mp 176–177 8C
10.03 (1H, s, OH); nmax (KBr) 2253, 1705 cmK1
.
4.2.2. Ethyl 8-hydroxy-2-imino-2H-chromene-3-car-
boxylate 8b and 8-hydroxy-2-oxo-2H-chromene-3-
carbonitrile 9b. Prepared from 2,3-dihydroxybenzaldehyde
1d (690 mg, 5 mmol) and ethyl cyanoacetate 5 (0.55 mL,
5 mmol). Compound 8b was precipitated from the reaction
mixture in 84% (979 mg) yield as a yellow solid; mp 225–
226 8C (EtOH). EI-MS: m/zZ233 (MC). 1H NMR (DMSO-
d6): 1.32 (3H, t, JZ7.1 Hz, CH2CH3); 4.29 (2H, q, JZ
7.1 Hz, CH2CH3); 7.06 (3H, m, H5, H6, H7); 8.67 (1H, s,
H4); 8.90 (1H, s, NH). (Found: C, 61.96; H, 4.45; N, 5.90.
C12H11NO4 requires: C, 61.80; H, 4.75; N, 6.01); nmax (KBr)
3297, 1703, 1600 cmK1. Compound 9b was isolated using
column chromatography (CH2Cl2/MeOH, 100:1) on the
residue from the evaporated residue. It was isolated in 1%
(9 mg) yield as a yellow solid; mp 228–230 8C (EtOH);
(mp21 238–240 8C). EI-MS: m/zZ187 (MC). 1H NMR
(DMSO-d6): 7.24–7.44 (3H, m, H5, H6, H7); 8.87 (s, 1H,
1
(EtOH). EI-MS: m/zZ200 (MC). H NMR (DMSO-d6):
3.85 (3H, s, OCH3); 6.75 (1H, d, JZ2.4 Hz, H8); 6.86 (1H,
dd, JZ8.7, 2.4 Hz, H6); 7.51 (1H, d, JZ8.7 Hz, H5); 8.41
(1H, s, H4); 8.65 (1H, s, NH). (Found: C, 65.77; H, 4.33; N,
14.23. C11H8N2O2 requires: C, 65.99; H, 4.03; N, 13.99);
nmax (KBr) 3293, 2221, 1654 cmK1
.
4.1.6. 6-Bromo-2-imino-2H-chromene-3-carbonitrile 4f.
Prepared from 5-bromo-2-hydroxybenzaldehyde 1f
(1005 mg, 5 mmol) and malononitrile 2 (330 mg, 5 mmol)
in 71% (884 mg) yield as a white solid; mp 198–199 8C
1
(EtOH). EI-MS: m/zZ248 (MC). H NMR (DMSO-d6):
7.16 (1H, d, JZ9.0 Hz, H8); 7.70–7.73 (1H, m, H7); 7.81–
7.82 (1H, m, H5); 8.29 (1H, d, JZ1.5 Hz, H4); 8.98 (1H, s,
NH). (Found: C, 48.10; H, 2.30; N, 11.33. C10H5N2OBr
requires: C, 48.22; H, 2.02; N, 11.24); nmax (KBr) 3310,
H4); nmax (KBr) 2253, 1746 cmK1
.
2231, 1648 cmK1
.
4.2.3. Ethyl 7-hydroxy-2-imino-2H-chromene-3-car-
boxylate 8c. Prepared from 2,4-dihydroxybenzaldehyde
1c (690 mg, 5 mmol) and ethyl cyanoacetate 5 (0.55 mL,
5 mmol). Compound 8c was precipitated from the reaction
mixture in 91% (1060 mg) yield as a yellow solid; mp 220–
221 8C (EtOH). EI-MS: m/zZ233 (MC). 1H NMR (DMSO-
d6): 1.31 (3H, t, JZ7.1 Hz, CH2CH3); 4.28 (2H, q, JZ
7.1 Hz, CH2CH3); 6.43 (1H, m, H8); 6.57 (1H, dd, JZ8.7,
2.4 Hz, H6); 7.51 (1H, d, JZ8.7 Hz, H5); 8.21 (1H, s, H4);
9.23 (1H, s, NH). EI-HRMS: m/zZ233.0695 (MC);
C12H11NO4 requires: 233.0688 (MC); nmax (KBr) 3312,
4.1.7. 7-Diethylamino-2-imino-2H-chromene-3-carbo-
nitrile 4g. Prepared from 4-diethylamino-2-hydroxybenzal-
dehyde 1g (965 mg, 5 mmol) and malononitrile 2 (330 mg,
5 mmol) in 51% (615 mg) yield as a yellow solid; mp 192–
193 8C (EtOH). EI-MS: m/zZ241 (MC). 1H NMR (DMSO-
d6): 1.11 (6H, t, JZ7.2 Hz, 2!CH2CH3); 3.43 (4H, q, JZ
7.2 Hz, 2!CH2CH3); 6.30–6.31 (1H, m, H8); 6.59–6.61
(1H, m, H6); 7.31 (1H, d, JZ9.0 Hz, H5); 8.06 (1H, s, H4);
8.19 (1H, s, NH). EI-HRMS: m/zZ241.1215 (MC);
C14H15N3O requires: 241.1212 (MC); nmax (KBr) 3342,
2218, 1630 cmK1
.
1693, 1630 cmK1
.
4.2. General procedure for the Knoevenagel reaction
between 2-hydroxybenzaldehyde derivatives and ethyl
cyanoacetate
4.2.4. 7-Diethylamino-2-oxo-2H-chromene-3-carbo-
nitrile 9d. Prepared from 4-diethylamino-2-hydroxy-
benzaldehyde 1g (965 mg, 5 mmol) and ethyl
cyanoacetate 5 (0.55 mL, 5 mmol). Compound 9d was
precipitated from the reaction mixture in 78% (944 mg)
yield as a yellow solid; mp 211–212 8C (EtOH). EI-MS:
A mixture of substituted 2-hydroxybenzaldehyde 1
(5 mmol) and ethyl cyanoacetate 5 (5 mmol) was dissolved
in 5 mL of ethanol, one drop of piperidine was added. The
reaction mixture was stirred at rt for 30 min. The product
precipitated from the reaction mixture and was collected by
filtration. The residue filtrate was evaporated in vacuo and
purified by column chromatography.
1
m/zZ242 (MC). H NMR (DMSO-d6): 1.25 (6H, t, JZ
6.9 Hz, 2!CH2CH3); 3.46 (4H, q, JZ7.2 Hz, 2!
CH2CH3); 6.46 (1H, d, JZ2.1 Hz, H8); 6.63 (1H, dd, JZ
9.0, 2.4 Hz, H6); 7.30 (1H, d, JZ9.0 Hz, H5); 7.96 (1H, s,

7018
J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
H4). (Found: C, 69.22; H, 5.84; N, 11.67. C14H14N2O2
requires: C, 69.40; H, 5.82; N, 11.56); nmax (KBr) 2218,
4.3.2. 2-(Chloroimino)-6-hydroxy-2H-chromene-3-car-
bonitrile 11b and 5-chloro-2-(chloroimino)-6-hydroxy-
2H-chromene-3-carbonitrile 12b. 6-Hydroxy-2-imino-
2H-chromene-3-carbonitrile 4b (935 mg, 5 mmol) and
13% NaOCl (15 mL) were reacted together in the standard
conditions. The yellow solid precipitated was purified by
column chromatography (CH2Cl2/MeOH, 1:1) to give
products 11b (451 mg, 41%) and 12b (141 mg, 11%).
Compound 11b had mp 209–210 8C (ethyl acetate). EI-MS:
1717 cmK1
.
4.2.5. 7-Methoxy-2-oxo-2H-chromene-3-carbonitrile 9e
and ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate
10e. Prepared from 2-hydroxy-4-methoxybenzaldehyde 1e
(760 mg, 5 mmol) and ethyl cyanoacetate 5 (0.55 mL,
5 mmol). Compound 9e was precipitated from the reaction
mixture in 85% (855 mg) yield as a white solid; mp 225–
226 8C (EtOH). EI-MS: m/zZ201 (MC). 1H NMR (DMSO-
d6): 3.92 (3H, s, OCH3); 7.07 (1H, dd, JZ2.4, 8.7 Hz, H6);
7.12 (1H, d, JZ2.4 Hz, H8); 7.73 (1H, d, JZ8.7 Hz, H5);
8.84 (1H, s, H4). (Found: C, 65.84; H, 3.54; N, 6.61.
C11H7NO3 requires: C, 65.67; H, 3.51; N, 6.96); nmax (KBr)
2228, 1724 cmK1. Compound 10e was isolated using
column chromatography (CH2Cl2/MeOH, 200:1) on the
residue from the evaporate residue. It was isolated in 3%
(38 mg) yield as a white solid; mp 132–133 8C (EtOH). EI-
MS: m/zZ248 (MC). 1H NMR (DMSO-d6): 1.30 (3H, t, JZ
7.2 Hz, CH3CH2); 3.89 (3H, s, OCH3); 4.28 (2H, q, JZ
7.2 Hz, CH3CH2); 6.99–7.04 (2H, m, H6, H8); 7.85 (1H, d,
JZ8.4 Hz, H5); 8.72 (s, 1H, H4). (Found: C, 62.79; H, 4.77.
C13H12O5 requires: C, 62.90; H, 4.87); nmax (KBr) 1750,
1
m/zZ220 (MC). H NMR (DMSO-d6): 7.04 (1H, d, JZ
3.0 Hz, H5); 7.10 (1H, dd, JZ9.0, 3.0 Hz, H7); 7.31 (d, 1H,
JZ9.0 Hz, H8); 8.44 (1H, s, H4); 10.06 (1H, s, OH). 13C
NMR (DMSO-d6): d 101.7, 113.8, 113.9, 116.8, 118.1,
122.1, 145.23, 145.8, 154.8, 157.9. (Found: C, 54.82; H,
2.30; N, 12.57. C10H5N2O2Cl requires: C, 54.44; H, 2.28; N,
12.70); nmax (KBr) 3340, 2249, 1654 cmK1. Compound 12b
had mp 204–205 8C (CH2Cl2). EI-MS: m/zZ254 (MC). 1H
NMR (DMSO-d6): 7.28 (1H, d, JZ9.0 Hz, H7); 7.33 (1H, d,
JZ9.0 Hz, H8); 8.49 (1H, s, H4); 10.06 (1H, s, OH). (Found:
C, 47.01; H, 1.51; N, 10.60. C10H4N2O2Cl2 requires: C, 47.09;
H, 1.58; N, 10.98); nmax (KBr) 3058, 2237, 1619 cmK1
.
4.3.3. 2-(Chloroimino)-7-hydroxy-2H-chromene-3-car-
bonitrile 11c. This was prepared from 7-hydroxy-2-
imino-2H-chromene-3-carbonitrile 4c (935 mg, 5 mmol)
and 13% NaOCl (15 mL) in 48% (528 mg) yield as a
yellow solid. It was purified by column chromatography
(CHCl3) and had mp 210–211 8C (CH2Cl2). EI-MS: m/zZ
1619 cmK1
.
4.2.6. Ethyl 6-bromo-2-oxo-2H-chromene-3-carboxylate
10f. Prepared from 5-bromo-2-hydroxybenzaldehyde 1f
(1005 mg, 5 mmol) and ethyl cyanoacetate 5 (0.55 mL,
5 mmol) in 44% (651 mg) yield as a white solid; mp 180–
181 8C (EtOH). EI-MS: m/zZ296 (MC). 1H NMR (DMSO-
d6): 1.31 (3H, t, JZ7.2 Hz, CH3CH2); 4.30 (2H, q, JZ
7.2 Hz, CH3CH2); 7.42 (1H, d, JZ8.7 Hz, H8); 7.88 (1H,
dd, JZ8.7, 2.4 Hz, H7); 8.17 (1H, d, JZ2.4 Hz, H5); 8.71
(1H, s, H4). (Found: C, 48.78; H, 3.10. C12H9O4Br requires:
1
220 (MC). H NMR (DMSO-d6): 7.04 (1H, d, JZ2.4 Hz,
H8); 6.81 (1H, dd, JZ8.4, 2.4 Hz, H6); 7.53 (d, 1H, JZ
8.4 Hz, H5); 8.36 (1H, s, H4); 11.17 (1H, s, OH). (Found: C,
54.34; H, 2.29; N, 12.35. C10H5N2O2Cl requires: C, 54.44;
H, 2.28; N, 12.70); nmax (KBr) 3294, 2243, 1633 cmK1
.
4.3.4. 2-(Chloroimino)-8-hydroxy-2H-chromene-3-car-
bonitrile 11d. This was prepared from 8-hydroxy-2-
imino-2H-chromene-3-carbonitrile 4d (935 mg, 5 mmol)
and 13% NaOCl (10 mL) in 52% (572 mg) yield as a yellow
solid. It was purified by column chromatography (CH2Cl2/
heptane, 1:4) and had mp 210–211 8C (CH2Cl2). EI-MS:
C, 48.51; H, 3.05); nmax (KBr) 1729, 1662 cmK1
.
4.3. General procedure for the preparation of N-chloro-
benzpyran-2-imine
1
m/zZ220 (MC). H NMR (DMSO-d6): 7.09–7.12 (1H, m,
A solution of the benzopyran-2-imine derivative (5 mmol)
in 8 mL of acetonitrile was cooled in an ice bath to 0 8C. A
13% solution of sodium chlorate was added dropwise during
a period of 10 min. Whilst the pH of the reaction mixture
was simultaneously adjusted to 5–6 using a 2.5 M solution
of H2SO4. The reaction mixture was stirred for an additional
10 min at 0 8C. Ice cold water (50 mL) was added to the
reaction mixture on which the product precipitated. It was
collected by filtration and chromatographed on a silica gel
column with an appropriate eluent. The following com-
pounds were prepared in this manner:
H7); 7.18–7.22 (2H, m, H6, H5); 8.44 (1H, s, H4); 10.58 (1H,
s, OH). (Found: C, 54.17; H, 2.27; N, 12.50. C10H5N2O2Cl
requires: C, 54.44; H, 2.28; N, 12.70); nmax (KBr) 3312,
2250, 1609 cmK1
.
4.3.5. 2-(Chloroimino)-7-methoxy-2H-chromene-3-car-
bonitrile 11e. This was prepared from 7-methoxy-2-
imino-2H-chromene-3-carbonitrile 4e (1000 mg, 5 mmol)
and 13% NaOCl (10 mL) in 41% (480 mg) yield as a white
solid. It was purified by column chromatography (CHCl3)
and had mp 224–225 8C (CHCl3). EI-MS: m/zZ234 (MC).
1H NMR (DMSO-d6): 3.91 (3H, s, OCH3); 7.00 (1H, dd, JZ
8.7, 2.4 Hz, H6); 7.06 (1H, d, JZ2.4 Hz, H8); 7.62 (1H, d,
JZ8.7 Hz, H6); 8.41 (1H, s, H4). (Found: C, 56.26; H, 3.19;
N, 12.17. C11H7N2O2Cl requires: C, 56.31; H, 3.01; N,
4.3.1. 2-(Chloroimino)-2H-chromene-3-carbonitrile 11a.
This was prepared from 2-imino-2H-chromene-3-carbo-
nitrile 4a (850 mg, 5 mmol) and 13% NaOCl (9 mL) in 40%
(408 mg) yield as a white solid. It was purified by column
chromatography (ethyl acetate/heptane, 1:1) and had mp
11.94); nmax (KBr) 2227, 1630 cmK1
.
1
191–192 8C (ethyl acetate). EI-MS: m/zZ204 (MC). H
4.3.6. 2-(Chloroimino)-6-bromo-2H-chromene-3-carbo-
nitrile 11f and 6-bromo-2-{[6-bromo-2-(chloroimino)-
3,3-dimethyl-3,4-dihydro-2H-chromene-4-yl]imino}-2H-
chromene-3-carbonitrile 13. 6-Bromo-2-imino-2H-chro-
mene-3-carbonitrile 4f (1005 mg, 5 mmol) and 13% NaOCl
NMR (DMSO-d6): 7.39–7.74 (4H, m, H5, H6, H7, H8); 8.51
(1H, s, H4). (Found: C, 58.89; H, 2.67; N, 13.73.
C10H5N2OCl requires: C, 58.70; H, 2.46; N, 13.69); nmax
(KBr) 2235, 1626 cmK1
.

J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
7019
(7 mL) were reacted together in the standard conditions. A
white solid precipitated which was purified by column
chromatography (CHCl3) to give product 11f (480 mg,
30%) and 13 (312 mg, 11%). Compound 11f had mp 200–
201 8C (CHCl3). EI-MS: m/zZ282 (MC). 1H NMR
(DMSO-d6): 7.44 (1H, d, JZ9.0 Hz, H8); 7.85 (1H, dd,
JZ9.0, 2.7 Hz, H7); 7.93 (1H, d, JZ2.7 Hz, H5); 8.40 (1H,
s, H4). (Found: C, 42.45; H, 1.18; N, 9.49. C10H4N2OClBr
requires: C, 42.36; H, 1.42; N, 9.88); nmax (KBr) 2238,
1662 cmK1. Compound 13 had mpO260 8C (ethyl acetate/
(1H, s, NH). (Found: C, 73.39; H, 4.58; N, 15.99.
C16H11N3O requires: C, 73.55; H, 4.24; N, 16.08); nmax
(KBr) 3292, 2238 cmK1
.
4.4.2. 6-Hydroxy-2-(phenylhydrazono)-2H-chromene-3-
carbonitrile 15b. This was prepared from 6-hydroxy-2-
imino-2H-chromene-3-carbonitrile 4b (558 mg, 3 mmol),
phenylhydrazine 14a (0.294 mL, 3 mmol) and NH4OAc
(270 mg, 3.5 mmol) in acetic acid (15 mL) as a red solid
(900 mg, 65%). It had mp 258–259 8C (e.g., acetic acid). EI-
MS: m/zZ277 (MC). 1H NMR (DMSO-d6): 6.72–6.77 (1H,
m, H04); 6.82 (1H, d, JZ3.0 Hz, H5); 6.91 (1H, dd, JZ8.7,
3.0 Hz, H7); 7.09 (1H, d, JZ8.7 Hz, H8); 7.13–7.16 (2H, m,
H02, H06); 7.20–7.25 (2H, m, H03, H05); 7.75 (1H, s, H4); 9.51
(1H, s, NH); 9.75 (1H, s, OH). (Found: C, 69.07; H, 4.10; N,
15.12. C16H11N3O2 requires: C, 69.31; H, 3.99; N, 15.15);
1
toluene, 1:1). EI-MS: m/zZ564 (MC). H NMR (DMSO-
d6): 5.99 (1H, s, H04); 7.40 (1H, d, JZ3.0 Hz, H05); 7.68
(1H, d, JZ8.7 Hz, H08); 7.70–7.74 (1H, m, H07); 7.91 (1H,
d, JZ2.7 Hz, H5); 7.96 (1H, dd, JZ9.0, 2.7 Hz, H7); 8.07–
8.08 (1H, m, H8); 8.34 (1H, s, H4); nmax (KBr) 2232,
1650 cmK1
.
nmax (KBr) 3313, 2250 cmK1
.
4.3.7. Ethyl 2-(Chloroimino)-6-hydroxy-2H-chromene-
3-carboxylate 11g and ethyl 5-chloro-2-(chloroimino)-6-
hydroxy-2H-chromene-3-carboxylate 12g. Ethyl
4.4.3. 8-Hydroxy-2-(phenylhydrazono)-2H-chromene-3-
carbonitrile 15c. This was prepared from 8-hydroxy-2-
imino-2H-chromene-3-carbonitrile 4d (558 mg, 3 mmol),
phenylhydrazine 14a (0.294 mL, 3 mmol) and NH4OAc
(270 mg, 3.5 mmol) in acetic acid (15 mL) as a red solid
(316 mg, 38%). It had mpO260 8C (e.g., acetic acid). EI-
MS: m/zZ277 (MC). 1H NMR (DMSO-d6): 6.77–6.82 (1H,
m, H04); 6.88–6.91 (1H, m, H7), 7.01–7.05 (2H, m, H5, H6);
7.08–7.11 (2H, m, H02, H06); 7.24–2.29 (2H, m, H03, H05);
7.77 (1H, s, H4); 9.73 (s, 2H, NH, OH). (Found: C, 69.38; H,
4.14; N, 14.81. C16H11N3O2 requires: C, 69.31; H, 3.99; N,
6-hydroxy-2-imino-2H-chromene-3-carboxylate
8a
(1165 mg, 5 mmol) and 13% NaOCl (16 mL) were reacted
together in the standard conditions. A yellow solid
precipitated which was purified by column chromatography
(CH2Cl2/MeOH, 100:1) to give 11g (346 mg, 26%) and 12g
(196 mg, 13%). Compound 11g had mp 176–177 8C
1
(CH2Cl2). EI-MS: m/zZ267 (MC). H NMR (DMSO-d6):
1.29 (3H, t, JZ7.2 Hz, CH3CH2); 4.28 (2H, q, JZ7.2 Hz,
CH3CH2); 7.03 (1H, dd, JZ8.7, 3.0 Hz, H7); 7.08 (1H, d,
JZ2.7 Hz, H5); 7.27 (1H, d, JZ8.7 Hz, H8); 8.05 (1H, s,
H4); 9.86 (1H, s, OH). 13C NMR (DMSO-d6): d 14.9, 62.4,
115.0, 117.3, 119.5, 121.2, 121.7, 139.4, 146.3, 155.3,
158.7, 163.6. (Found: C, 50.84; H, 3.95; N, 4.77.
C12H10NO4Cl!H2O requires: C, 50.45; H, 4.23; N, 4.90);
nmax (KBr) 3321, 1713, 1747 cmK1. Compound 12g had mp
15.15); nmax (KBr) 3326, 2241 cmK1
.
4.4.4. 7-Methoxy-2-(phenylhydrazono)-2H-chromene-3-
carbonitrile 15d. This was prepared from 7-methoxy-2-
imino-2H-chromene-3-carbonitrile 4e (600 mg, 3 mmol),
phenylhydrazine 14a (0.294 mL, 3 mmol) and NH4OAc
(270 mg, 3.5 mmol) in acetic acid (15 mL) as a red solid
(411 mg, 47%). It had mp 247–248 8C (e.g., acetic acid). EI-
1
152–153 8C (CH2Cl2). EI-MS: m/zZ301 (MC). H NMR
(DMSO-d6): 1.30 (3H, t, JZ7.2 Hz, CH3CH2); 4.30 (2H, q,
JZ7.2 Hz, CH3CH2); 7.24 (1H, d, JZ9.0 Hz, H7); 7.29
(1H, dd, JZ9.0, 0.9 Hz, H8); 8.06 (1H, d, JZ0.9 Hz, H4);
10.65 (1H, s, OH). (Found: C, 46.37; H, 3.11; N, 4.21.
C12H9NO4Cl2!1⁄2H2O requires: C, 46.33; H, 3.24; N, 4.50);
1
MS: m/zZ291 (MC). H NMR (DMSO-d6): 3.86 (3H, s,
OCH3); 6.73–6.83 (3H, m H04, H6, H8); 7.12–7.15 (2H, m,
H02, H06); 7.20–7.25 (2H, m, H03, H05); 7.39 (1H, dd, JZ
9.0 Hz, H5); 7.76 (1H, s, H4); 9.50 (1H, s, NH). (Found: C,
69.88; H, 4.31; N, 14.35. C17H13N3O2 requires: C, 70.09; H,
nmax (KBr) 3319, 1725, 1760 cmK1
.
4.50; N, 14.42); nmax (KBr) 3305, 2230 cmK1
.
4.4. General procedure for the preparation of
N-hydrazono-benzpyran-2-imine
4.4.5. Ethyl 6-hydroxy-2-(phenylhydrazono)-2H-chro-
mene-3-carboxylate 15e. This was prepared from
A mixture of benzopyran-2-imine derivatives (3 mmol),
hydrazine derivatives (3 mmol) and NH4OAc (3.5 mmol) or
NaOAc (3 mmol) was dissolved in 15 mL of acetic acid and
stirred at rt for 1 h. The product precipitated from the
reaction mixture and was collected by filtration. It was
recrystallized from an appropriate solvent. The following
compounds were prepared in this manner.
6-hydroxy-2-imino-2H-chromene-3-carboxylate
8a
(699 mg, 3 mmol), phenylhydrazine 14a (0.294 mL,
3 mmol) and NH4OAc (270 mg, 3.5 mmol) in acetic acid
(15 mL) as a red solid (302 mg, 31%). It had mp 178–179 8C
(e.g., acetic acid). EI-MS: m/zZ324 (MC). 1H NMR
(DMSO-d6): 1.34 (3H, t, JZ7.2 Hz, CH2CH3); 4.30 (2H,
q, JZ7.2 Hz, CH2CH3); 6.68–6.73 (1H, m, H04); 6.82–7.08
(3H, m, H5, H7, H8); 7.10–7.13 (2H, m, H02, H06); 7.16–7.18
(2H, m, H03, H05); 7.36 (1H, s, H4); 9.38 (1H, s, NH); 9.58
(rs, 1H, OH). (Found: C, 67.02; H, 5.30; N, 9.02.
C18H16N2O4 requires: C, 66.66; H, 4.97; N, 8.64); nmax
4.4.1. 2-(Phenylhydrazono)-2H-chromene-3-carbonitrile
15a. This was prepared from 2-imino-2H-chromene-3-
carbonitrile 4a (510 mg, 3 mmol), phenylhydrazine 14a
(0.294 mL, 3 mmol) and NH4OAc (270 mg, 3.5 mmol) in
acetic acid (15 mL) as a red solid (483 mg, 37%). It had mp
205–206 8C (e.g., acetic acid). EI-MS: m/zZ261 (MC). 1H
NMR (DMSO-d6): 6.74–6.80 (1H, m, H04); 7.14–7.18 (2H,
m, H02, H06); 7.20–7.26 (4H, m, H5, H6, H03, H05); 7.43–7.46
(1H, m, H8); 7.49–7.55 (1H, m, H7); 7.80 (1H, s, H4); 9.61
(KBr) 3378, 1678 cmK1
.
4.4.6. Ethyl 8-hydroxy-2-(phenylhydrazono)-2H-chro-
mene-3-carboxylate 15f. This was prepared from
8-hydroxy-2-imino-2H-chromene-3-carboxylate 8b
(699 mg, 3 mmol), phenylhydrazine 14a (0.294 mL,

7020
J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
3 mmol) and NH4OAc (270 mg, 3.5 mmol) in acetic acid
(15 mL) as red solid (622 mg, 64%). It had mp 208–209 8C
(e.g., acetic acid). EI-MS: m/zZ324 (MC). 1H NMR
(DMSO-d6): 1.34 (3H, t, JZ7.2 Hz, CH2CH3); 4.31 (2H,
q, JZ7.2 Hz, CH2CH3); 6.72–6.78 (1H, m, H04); 6.95–6.98
(3H, m, H5, H6, H7); 7.06–7.09 (2H, m, H02, H06); 7.20–7.25
(2H, m, H03, H05); 7.40 (1H, s, H4); 9.68 (2H, s, OH, NH).
13C NMR (DMSO-d6): d 14.4, 61.4, 112.5, 119.1, 119.5,
119.8, 120.2, 122.7, 124.5, 129.41, 131.47, 135.9, 140.9,
144.1, 145.5, 164.0. (Found: C, 63.19; H, 5.13; N, 7.99.
C18H16N2O4!H2O requires: C, 63.15; H, 5.30; N, 8.18);
(DMSO-d6): 1.34 (3H, t, JZ7.2 Hz, CH2CH3); 4.31 (2H,
q, JZ7.2 Hz, CH2CH3); 6.74–6.78 (1H, m, H05); 6.93–7.04
(3H, m, H5, H6, H7); 7.10–7.13 (1H, m, H03); 7.51 (1H, s,
H4); 7.61–7.67 (1H, m, H04); 8.11–8.13 (1H, m, H06); 10.60
(1H, s, NH). (Found: C, 63.00; H, 4.72; N, 12.66.
C17H15N3O4 requires: C, 62.76; H, 4.65; N, 12.92); nmax
(KBr) 1697, 1673 cmK1
.
4.4.11. 2-[(Anilinocarbonyl)hydrazono]-2H-chromene-
3-carbonitrile 17a. This was prepared from 2-imino-2H-
chromene-3-carbonitrile 4a (170 mg, 1 mmol), N-phenyl-
hydrazinecarboxamide 14c (151 mg, 1 mmol) and NaOAc
(82 mg, 1 mmol) in acetic acid (5 mL) as a yellow solid
(95 mg, 31%). It had mpO260 8C (e.g., acetic acid). EI-MS:
nmax (KBr) 3395, 1717 cmK1
.
4.4.7. 2-(Pyridin-2-ylhydrazono)-2H-chromene-3-carbo-
nitrile 16a. This was prepared from 2-imino-2H-chromene-
3-carbonitrile 4a (170 mg, 1 mmol), 2-hydrazinopyridine
14b (109 mg, 1 mmol) and NH4OAc (115 mg, 1.5 mmol) in
acetic acid (5 mL) as a red solid (127 mg, 48%). It had mp
164–165 8C (e.g., acetic acid). EI-MS: m/zZ262 (MC). 1H
NMR (DMSO-d6): 6.78–6.82 (1H, m, H05); 7.12–7.15 (1H,
m, H8); 7.19–7.25 (1H, m, H6); 7.34–7.37 (1H, m, H03); 7.47
(1H, dd, JZ7.5, 1.5 Hz, H5); 7.50–7.56 (1H, m, H04); 7.65–
7.71 (1H, m, H7); 7.93 (1H, s, H4); 8.13–8.15 (1H, m, H06);
9.97 (1H, s, NH). (Found: C, 68.56; H, 3.92; N, 20.96.
C15H10N4O requires: C, 68.69; H, 3.84; N, 21.36); nmax
1
m/zZ304 (MC). H NMR (DMSO-d6): 6.98–7.04 (1H, m,
H04); 7.27–7.33 (4H, m, H5, H6, H7, H8); 7.48–7.52 (2H, m,
H02, H06); 7.54–7.61 (2H, m, H03, H05); 8.09 (1H, s, H4); 8.74
(1H, s, NH); 10.07 (1H, s, NH). (Found: C, 67.43; H, 3.81;
N, 18.13. C17H12N4O2 requires: C, 67.10; H, 3.97; N,
18.41); nmax (KBr) 3379, 2236, 1704 cmK1
.
4.4.12. 2-[(Anilinocarbonyl)hydrazono]-6-hydroxy-2H-
chromene-3-carbonitrile 17b. This was prepared from
6-hydroxy-2-imino-2H-chromene-3-carbonitrile
4b
(186 mg, 1 mmol), N-phenylhydrazinecarboxamide 14c
(151 mg, 1 mmol) and NaOAc (82 mg, 1 mmol) in acetic
acid (5 mL) as a yellow solid (218 mg, 68%). It had mp
(KBr) 2299, 1598 cmK1
.
1
4.4.8. 6-Hydroxy-2-(pyridin-2-ylhydrazono)-2H-chro-
mene-3-carbonitrile 16b. This was prepared from
O260 8C (e.g., acetic acid). EI-MS: m/zZ320 (MC). H
NMR (DMSO-d6): 6.89 (1H, d, JZ3.0 Hz, H5); 7.96–7.03
(2H, m, H7, H04); 7.15 (1H, d, JZ8.7 Hz, H8); 7.27–7.32
(2H, m, H03, H05); 7.48–7.51 (2H, m, H02, H06); 8.03 (1H, s,
H4); 8.72 (1H, br s, NH); 9.97 (1H, br s, NH). HRMS: m/z
320.0909 (MC, Calcd 320.0910 for C17H12N4O3); nmax
6-hydroxy-2-imino-2H-chromene-3-carbonitrile
4b
(186 mg, 1 mmol), 2-hydrazinopyridine 14b (109 mg,
1 mmol) and NH4OAc (115 mg, 1.5 mmol) in acetic acid
(5 mL) as a red solid (113 mg, 40%). It had mp 246–247 8C
(e.g., acetic acid). EI-MS: m/zZ278 (MC). 1H NMR
(DMSO-d6): 6.76–6.79 (1H, m, H05); 6.84 (1H, d, JZ
3.0 Hz, H5); 6.92 (1H, dd, JZ9.0, 3.0 Hz, H7); 7.10–7.13
(1H, m, H03); 7.20 (1H, d, JZ9.0 Hz, H8); 7.64–7.70 (1H,
m, H04); 7.87 (1H, s, H4); 8.11–8.14 (1H, m, H06); 8.29 (1H,
br s, OH); 9.82 (1H, br s, NH). HRMS: m/z 278.0811 (MC,
Calcd 278.0803 for C15H10N4O2); nmax (KBr) 2232,
(KBr) 3377, 2237, 1728 cmK1
.
4.4.13. 2-[(Anilinocarbonyl)hydrazono]-8-hydroxy-2H-
chromene-3-carbonitrile 17c. This was prepared from
8-hydroxy-2-imino-2H-chromene-3-carbonitrile
4d
(186 mg, 1 mmol), N-phenylhydrazinecarboxamide 14c
(151 mg, 1 mmol) and NaOAc (82 mg, 1 mmol) in acetic
acid (5 mL) as a yellow solid (170 mg, 53%). It had mp O
260 8C (e.g., acetic acid). EI-MS: m/zZ320 (MC). 1H NMR
(DMSO-d6): 7.95–7.10 (4H, m, H5, H6, H7, H04); 7.27–7.33
(2H, m, H03, H05); 7.53–7.56 (2H, m, H02, H06); 8.05
(1H, s, H4); 8.82 (1H, br s, N H); 10.72 (1H, br s, NH).
(Found: C, 61.64; H, 4.22; N, 16.40. C17H12N4O3!
1⁄2AcOH requires: C, 61.71; H, 4.03; N, 15.99); nmax (KBr)
1654 cmK1
.
4.4.9. 8-Hydroxy-2-(pyridin-2-ylhydrazono)-2H-chro-
mene-3-carbonitrile 16c. This was prepared from
8-hydroxy-2-imino-2H-chromene-3-carbonitrile
4d
(186 mg, 1 mmol), 2-hydrazinopyridine 14b (109 mg,
1 mmol) and NH4OAc (115 mg, 1.5 mmol) in acetc acid
(5 mL) as a red solid (106 mg, 38%). It had mp 255–256 8C
(e.g., acetic acid). EI-MS: m/zZ278 (MC). 1H NMR
(DMSO-d6): 6.78–6.82 (1H, m, H05); 6.91 (1H, d, JZ6.9,
2.4 Hz H5); 6.99–7.04 (2H, m, H6, H7); 7.13–7.16 (1H, m,
H03); 7.69–7.72 (1H, m, H04); 7.87 (1H, s, H4); 8.15 (1H, m,
H06); 10.64 (1H, s, NH). (Found: C, 60.32; H, 4.27; N,
16.27. C15H10N4O2!AcOH requires: C, 60.35; H, 4.17; N,
3366, 2231, 1687 cmK1
.
4.4.14. Ethyl 2-[(anilinocarbonyl)hydrazono]-6-
hydroxy-2H-chromene-3-carboxylate 17d. This was pre-
pared from 6-hydroxy-2-imino-2H-chromene-3-carboxylate
8a (233 mg, 1 mmol), N-phenylhydrazinecarboxamide 14c
(151 mg, 1 mmol) and NaOAc (82 mg, 1 mmol) in acetic
acid (5 mL) as a yellow solid (250 mg, 68%). It had mp
231–232 8C (e.g., acetic acid). EI-MS: m/zZ367 (MC). 1H
NMR (DMSO-d6): 1.33 (3H, t, JZ7.2 Hz, CH2CH3); 4.33
(2H, q, JZ7.2 Hz, CH2CH3); 6.90–6.95 (m, 2H, H5, H7);
6.98–7.03 (1H, m, H04); 7.18 (1H, d, JZ8.4 Hz, H8); 7.28–
7.33 (2H, m, H03, H05); 7.48–7.52 (2H, m, H02, H06); 7.74
(1H, s, H4); 8.58 (1H, s, NH); 10.04 (1H, s, NH). 13C NMR
(DMSO-d6): d 14.4, 21.5, 61.6, 114.5, 116.5, 119.0, 119.2,
119.9, 120.9, 122.7, 129.2, 136.2, 138.9, 139.2, 146.1,
16.56); nmax (KBr) 2299, 1598 cmK1
.
4.4.10. Ethyl 8-hydroxy-2-(pyridin-2-ylhydrazono)-2H-
chromene-3-carboxylate 16d. This was prepared from
8-hydroxy-2-imino-2H-chromene-3-carboxylate
8b
(233 mg, 1 mmol), 2-hydrazinopyridine 14b (109 mg,
1 mmol) and NH4OAc (115 mg, 1.5 mmol) in acetc acid
(5 mL) as a red solid (160 mg, 49%). It had mp 146–147 8C
(e.g., acetic acid). EI-MS: m/zZ325 (MC). 1H NMR

J. Volmajer et al. / Tetrahedron 61 (2005) 7012–7021
7021
153.1, 154.0, 163.4, 172.5. (Found: C, 62.33; H, 4.52; N,
11.52. C19H17N3O5 requires: C, 62.12; H, 4.66; N, 11.44);
nmax (KBr) 3391, 1712, 1682 cmK1
References and notes
.
1. Maxwell, A. Mol. Microbiol. 1993, 9, 681–686.
2. Abd-Allah, O. A. Farmaco 2000, 55, 641–649.
4.4.15.
Ethyl
2-[(anilinocarbonyl)hydrazono]-8-
3. El-Agrody, A. M.; El-Latif, M. S. A.; El-Hady, N. A.; Fakary,
A. H.; Bedair, A. H. Molecules 2001, 6, 519–527.
4. Emmanuel-Giota, A. A.; Fylaktakidou, K. C.; Hadjipavlou-
Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. J. Heterocycl.
Chem. 2001, 38, 717–722.
hydroxy-2H-chromene-3-carboxylate 17e. This was pre-
pared from 8-hydroxy-2-imino-2H-chromene-3-carboxylate
8b (233 mg, 1 mmol), N-phenylhydrazinecarboxamide 14c
(151 mg, 1 mmol) and NaOAc (82 mg, 1 mmol) in acetic
acid (5 mL) as a yellow solid (334 mg, 91%). It had mp
226–227 8C (e.g., acetic acid). EI-MS: m/zZ367 (MC). 1H
NMR (DMSO-d6): 1.33 (3H, t, JZ6.9 Hz, CH2CH3); 4.34
(2H, q, JZ6.9 Hz, CH2CH3); 7.00–7.07 (m, 4H, H5, H6, H7,
H04); 7.29–7.34 (2H, m, H03, H05); 7.52–7.55 (2H, m, H02,
H06); 7.78 (1H, s, H4); 8.62 (1H, br s, NH); 10.65 (1H, br s,
NH); 12.00 (1H, br s, OH). (Found: C, 62.32; H, 4.52; N,
11.17. C19H17N3O5 requires: C, 62.12; H, 4.66; N, 11.44);
5. Manolov, I.; Danchev, N. D. Eur. J. Med. Chem. 1995, 30,
531–536.
6. Dexeus, F. H.; Logothetis, C. J.; Sella, A.; Fitz, K.; Amato, R.;
Reuben, J. M.; Dozier, N. J. Clin. Oncol. 1990, 8, 325–329.
7. Nofal, Z. M.; El-Zahar, M. I.; El-Karim, S. S. A. Molecules
2000, 5, 99–113.
8. Haugland, R. P. Handbook of Fluorescent Probes and
Research Products, 9th ed.; Molecular probes: Eugene, 2002.
9. Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A., Rees, C. W., Scriven,
E. F. V., Eds.; Pyrans and their benzo derivatives: applications;
Pergamon: Oxford, 1996; Vol. 5, Chapter 5.09, pp 469–500.
10. Burke, T. R.; Lim, B.; Marquez, V. E.; Li, Z.-H.; Bolen, J. B.;
Stefanova, I.; Horak, I. D. J. Med. Chem. 1993, 36, 425–432.
11. Huang, C. K.; Wu, F. Y.; Ai, Y. X. Bioorg. Med. Chem. Lett.
1995, 5, 2423–2428.
nmax (KBr) 3363, 1713, 1687 cmK1
.
4.4.16. 6-Hydroxy-2-(phenylhydrazono)-2H-chromene-
3-carbonitrile 15b and 2,5-dihydroxybenzaldehyde
phenylhydrazone 18. 6-Hydroxy-2-imino-2H-chromene-
3-carbonitrile 4b (558 mg, 3 mmol) and phenylhydrazine
14a (0.294 mL, 3 mmol) in acetic acid (15 mL) were
reacted together as usual. The red solid precipitated which
was purified by column chromatography (diethyl ether/
CH2Cl2, 1:20) to give product 15b (341 mg, 41%) and 18
(145 mg, 21%). Compound 15b had mp 258–259 8C (e.g.,
acetic acid). EI-MS: m/zZ277 (MC). 1H NMR (DMSO-d6):
6.72–6.77 (1H, m, H04); 6.82 (1H, d, JZ3.0 Hz, H5); 6.91
(1H, dd, JZ8.7, 3.0 Hz, H7); 7.09 (1H, d, JZ8.7 Hz, H8);
7.13–7.16 (2H, m, H02, H06); 7.20–7.25 (2H, m, H03, H05);
7.75 (1H, s, H4); 9.51 (1H, s, NH); 9.75 (1H, s, OH).
Compound 18 had mp 206–207 8C (EtOH). EI-MS: m/zZ
12. O’Callaghan, C. N.; Conalty, M. L. P. Roy. Irish Acad. 1979,
6, 87–98.
13. Volmajer, J.; Toplak, R.; Bittner, S.; Leban, I.; Majcen Le
Marechal, A. Tetrahedron Lett. 2003, 44, 2363–2366.
14. Padmanabhan, S.; Peri, R.; Triggle, D. J. Synth. Commun.
1996, 26, 827–831.
15. Silin, A. V.; Gorobetes, N. Y.; Sytnik, K. M.; Nikitchenko,
V. M. Visn. Khark. Univ. 1997, 395, 274–277. Chem. Abstr.
1998, 129, 290037.
228 (MC). H NMR (DMSO-d6): 6.58 (1H, dd, JZ8.7,
1
3.0 Hz, H4); 6.69 (1H, d, JZ8.7 Hz, H5); 6.73 (1H, t, JZ
7.2 Hz, H04); 6.97 (3H, m, H2, H02, H06); 7.23 (2H, m, H03,
H05); 8.06 (1H, s, CH); 8.79 (1H, s, NH); 9.71 (1H, s, OH);
10.31 (s, 1H, OH).). HRMS: m/z 228.0899 (MC, Calcd
16. O’Callaghan, C. N.; McMurry, T. B. H.; O’Brien, J. E.
J. Chem. Soc., Perkin Trans. 2 1998, 425–429.
17. Kovalenko, S. N.; Sytnik, K. M.; Nikitchenko, V. M.;
Rusanova, S. V.; Chernykh, V. P.; Porokhnyak, A. O. Chem.
Heterocycl. Compd. 1999, 35, 167–170.
228.0901 for C13H12N2O2); nmax (KBr) 3309, 1601 cmK1
.
18. Zubkov, V. A.; Kovalenko, S. N.; Chernykh, V. P.; Ivkov,
S. M. Chem. Heterocycl. Compd. 1994, 30, 665–670.
19. Mhiri, C.; El Gharbi, R.; Le Bigot, Y. Synth. Commun. 1999,
29, 3385–3399.
Acknowledgements
This research was supported by the Ministry of Education,
Science and Sport of Slovenia (L1-6018-04/795). We thank
Prof. Dr. Branko Stanovnik, Faculty of Chemistry and
Chemical Technology, Ljubljana, for elemental analysis,
20. Bruce, J. M.; Creed, D.; Dawes, K. J. Chem. Soc. (C) 1971,
3749.
21. Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Hetero-
cycles 1996, 43, 1257–1266.
ˇ
Prof. Dr. Andrej Petric, Faculty of Chemistry and Chemical
Technology, Ljubljana, for H NMR spectra, Dr. Bogdan
1
ˇ
Kralj, Institut Jozef Stefan, Ljubljana, for mass spec-
trometry and Prof. Dr. Dominique Lorcy, Universite de
Rennes 1, France, for 13C NMR spectra.