Meldrum's acid in heterocyclic synthesis: Azoles incorporating a 2,4-dichlorophenoxy moiety with anticipated molluscicidal activity

Article abstract of DOI:10.1007/s00706-007-0802-3

Synthesis of the title ring system is described using ethyl 4-(2,4-dichlorophenoxy)-3-oxobutanoate as starting material. The latter was prepared through acylating Meldrum's acid with the phenoxy acid chloride derivative.

Full text of DOI:10.1007/s00706-007-0802-3

Monatsh Chem 139, 685–689 (2008)
DOI 10.1007/s00706-007-0802-3
Printed in The Netherlands
Meldrum’s acid in heterocyclic synthesis: azoles incorporating
a 2,4-dichlorophenoxy moiety with anticipated molluscicidal activity
Emad M. El-Telbani, Mohamed F. El Shehry, Galal A. M. Nawwar
National Research Centre, Pesticides Department, Dokki, Cairo, Egypt
Received 7 August 2007; Accepted 13 September 2007; Published online 24 April 2008
# Springer-Verlag 2008
Abstract Synthesis of the title ring system is de-
scribed using ethyl 4-(2,4-dichlorophenoxy)-3-oxobu-
tanoate as starting material. The latter was prepared
through acylating Meldrum’s acid with the phenoxy
acid chloride derivative.
Results and discussion
Ethyl 4-(2,4-dichlorophenoxy)-3-oxo-butanoate (4)
seemed to be a suitable precursor to obtain the aimed
heterocycles. It was prepared by acylating Meldrum’s
acid 2 with 2,4-dichlorophenoxyacetyl chloride (1)
to give the acylated Meldrum’s acid 3. The chemical
behavior of 3 was in accordance with its structure.
Thus, a ꢀ-ketoester synthesis is achieved after re-
fluxing compound 3 in absolute ethanol to afford the
Keywords Meldrum’s acid; Acylation; 2,4-Dichlorophenox-
yacetic acid; Molluscicides.
1
Introduction
aimed acetate 4. Its H NMR spectrum revealed the
ethyl residue at ꢁ ¼ 4.3 (CH2ꢀ) and 1.3 (CH3ꢀ) ppm.
This procedure proved to be superior to the conven-
tional ꢀ-ketoester synthesis [6].
Search for new molluscicides is of continuous in-
terest as bilharziosis, which still is considered an
endemic disease in Egypt. In our previous work,
several azoles were proved to exhibit molluscici-
dal activity [1–4]. Meantime, 2,4-dichlorophenoxy
(2,4-D) moiety showed herbicidal activity [5]. So,
it seemed a good idea to prepare new azoles car-
rying the 2,4-D moiety hoping to synergize both
activities, for competing snails and the hyacinth
plant, which have many disadvantages: it is con-
sidered a biological shelter for the infected snails
that aggravates the problem, helps in the evapora-
tion and consumption of huge amounts of water
beside obstructing the navigation in the river Nile.
In addition, the ꢀ-ketoester 4 was treated with
phenylhydrazine in acetic acid, a new product was
formed showing the molecular ion peak at m=z (Mþ,
1
334). Its H NMR pattern lacked the ester group
protons-present in the parent 4 and showed instead
a new signal at ꢁ ¼ 3.75 ppm (2H) beside a multiplet
attributable to the phenyl protons. Accordingly, the
pyrazolone structure 5 was assigned to this product.
On applying a Claisen condensation to the pyr-
azolone 5, using ethyl formate in presence of sodium
ethoxide, the corresponding 3-[(2,4-dichlorophen-
oxy)methyl)]-5-hydroxy-1-phenyl-1H-pyrazole-4-
carbaldehyde (6a) was obtained. The detection of the
hydroxymethylene proton at ꢁ ¼ 8.20 ppm [7], sug-
gested the prescence of 6a principally, as hydroxyl
methylene tautomer.
Correspondence: Emad M. El-Telbani, Pesticides Depart-
ment, National Research Centre, Dokki, 12622 Cairo, Egypt.
E-mail: e_misbah@yahoo.co.uk

686
E. M. El-Telbani et al.
The pyrazolone 5 was also subjected to a Vilsmeir-
afforded the corresponding enaminone derivative
9. This structure assignment was based on microana-
Haack chloroformylation [8]. The product was iden-
tified as 5-chloro-3-[(2,4-dichlorophenoxy)methyl)]-
1-phenyl-1H-pyrazole-4-carbaldehyde (6b). Its mass
spectrum was in accordance with its molecular for-
mula (C17H11N2O2Cl3), along with a singlet proton
at ꢁ ¼ 10.0 ppm (formyl-H).
1
lytical and spectral data. So, its H NMR spectrum
showed the N,N-dimethyl group protons at ꢁ ¼
3.4 ppm together to the ylidene proton at ꢁ ¼ 7.90ppm.
Conversion of compound 9 to isoxazole derivative
10 was successfully achieved upon its treatment with
hydroxylamine hydrochloride in acetic acid. Its mass
spectral data revealed the molecular ion peak at
m=z (Mþ, 315) while the isoxazole H-5 was detected
at ꢁ ¼ 9.07 ppm. This formation probably proceeded
through the self cyclization of an initial oximino
intermediate with subsequent loss of dimethylamine
to yield 10 (cf. Scheme 1).
When the pyrazolone derivative 5 reacted with
sodium nitrite in the presence of acetic acid, 4-
hydroximino derivative 11 was obtained. It showed
the hydroxyl proton as a (D2O exchangeable) singlet
at ꢁ ¼ 7.6 ppm instead of the pyrazolone CH2 pro-
tons signal-previously detected in the parent.
On treating compound 6b with sodium azide in
DMSO in the dark, 5-azido derivative 7 was obtained
(cf. Experimental). This nucleophilic aromatic sub-
stitution proceeded smoothly probably due to the
presence of the electron withdrawing formyl substit-
uent in the o-position [9].
When the azide 7 was subjected to thermolysis by
heating in toluene, the reaction afforded a sole product
showing only an IR CN absorption and lacking the
aldehydic CO. Meantime, a new singlet was detected
in the latter at ꢁ ¼ 7.7 ppm (1H). Based on these data,
structure 8 was given to this product. This result does
not go along with a previous reports [10–12], that
when the azide group was ortho to an aldehyde group
in a pyrazole ring, the latter could be rearranged to a
furan ring when subjected to thermolysis.
The pyrazolone 5 also reacted with the benzylidene
ethylcyanoacetate 12 with the formation of a new
product showing IR CO absorption at 1660cmꢀ1.
Its mass spectral data revealed the molecular ion
peak at m=z (Mþ, 422), while it is 1H NMR spectrum
Treatment of compound 4 with N,N-dimethyl-
formamide dimethylacetal (DMF=DMA) in benzene
Scheme 1

Meldrum’s acid in heterocyclic synthesis
687
Scheme 2
showed beside two phenyl moieties, a new singlet
(1H) at ꢁ ¼ 7.94 ppm. Based on these spectroscopic
data, structure 14 is proposed instead of the expected
pyrazoloiminopyran structure 13, compound 14
probably formed via yilidene exchange [13].
Further work is in progress and will be published
elsewhere.
Experimental
Melting points were determined on an Electrothermal 9100
digital melting point apparatus IR, NMR, and mass spectra
were recorded on Pye-Unicam SP-1100, Jeol 270 MHz and
Jeol 500MHz, with internal standard tetramethylsilane (TMS),
and Jeol JMS-AX500. Elemental analysis (in accord with the
calculated values) were carried out in the microanalytical unit,
Faculty of Science, Cairo University. Precoated silica gel 60
F254 plates with a layer thickness 0.25 nm from Merck were
used for thin layer chromatography. Yields are not optimized.
Moreover, compound 5 was added to N,N-dimeth-
ylformamide dimethylacetal in toluene to yield the
4-dimethylaminomethylene derivative 15 the struc-
ture of which was deduced through microanalytical
and spectral data (cf. Experimental).
In contrast to the result previously obtained with
compound 9, when compound 15 was treated with
hydroxylamine hydrochloride, a nucleophilic substi-
tution of the dimethylamino group occurred to yield
5-[2-(2,4-Dichlorophenoxy)acetyl]-2,2-dimethyl-1,3-dioxane-
4,6-dione (3, C14H12O6Cl2)
1
compound 16. The H NMR of the latter showed
To a solution of 1.44 g 2 (10 mmol) in 10cm3 methylene
chloride in a 250 cm3 round-bottomed flask, equipped with an
addition funnel and nitrogen inlet and cooled to 0ꢁC, pyridine
(2.5cm3) was dropped for a period of 10min followed by
the addition of a freshly prepared solution of 2.39g 2,4-
dichlorophenoxy acetyl chloride 1 (10 mmol) in 15cm3 meth-
ylene chloride, which resulted in an orange solution. After
complete addition (ꢂ2 h), the resulting dark orange solution
was stirred for an additional hour. The solution was diluted
with methylene chloride (10 cm3) and poured onto 2 M HCl
and ice. The two phases were separated, and the aqueous
phase was extracted with methylene chloride (2ꢃ50cm3).
The combined organic phases were washed with 2 M HCl
(2ꢃ50 cm3), dried over anhydrous sodium sulphate, and evap-
orated. The resulting organic oil was solidified with pet. ether
40–60ꢁC, collected, washed with ether, and crystallized to give
(D2O exchangeable) broad singnal at ꢁ ¼ 3.75 ppm
attributable to the NH and OH group protons, re-
spectively, with absence of the dimethylamino group
protons present in 15.
Compound 15 was also treated with 2-chloro-4-
nitro-aniline in acetic acid: the formed product 17
showed the molecular peak at m=z (Mþ, 517) equiv-
alent to the sum of both reactants minus a dimethy-
lamino moiety. Accordingly, structure of compound
17 was given to this product which was also con-
firmed from the other elemental and spectral data (cf.
Scheme 2).
The preliminary molluscicidal testing showed that
compounds 5, 15, and 11 are the most promising.

688
E. M. El-Telbani et al.
3-[(2,4-Dichlorophenoxy)methyl]-4-[(hydroxyamino)-
3 (75%) as pale yellow crystals. Mp 112–113ꢁC (toluene); IR
(film): ꢂꢀ¼ 3009 (CH), 1735 (CO), 1660 (CO) cmꢀ1; 1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 1.79 (s, 6H, 2ꢃCH3), 4.0 (s, 1H,
CHꢀ), 5.10 (s, 2H, CH2), 7.13–7.49 (m, 3H, Ar–H) ppm; MS:
m=z (%) ¼ 346 [Mþ].
methylene]-1-phenyl-1,5-dihydropyrazol-5-one
(16, C17H13N3O3Cl2)
Colorless crystals, yield (65%), mp 192–194ꢁC (DMF); IR
(film): ꢂꢀ¼ 3420 (OH), 3115 (NH), 1720 (CO), 1590 (C¼N)
cmꢀ1; 1H NMR (500 MHz, DMSO-d6): ꢁ ¼ 3.75 (brs, 2H, OH,
NH), 5.17 (s, 2H, OCH2ꢀ), 7.70–7.56 (m, 9H, Ar–H, ¼CH)
ppm; MS: m=z (%) ¼ 378 [Mþ].
Ethyl-4-(2,4-dichlorophenoxy)-3-oxobutanoate
(4, C12H12O4Cl2)
A solution of 3.47 g 3 (10 mmol) in 50cm3 anhydrous ethanol
was refluxed for 2.5h. The solvent was removed in vacuo,
leading to a dark oil which was purified by column chroma-
tography (silica gel, ethyl acetate=pet. ether 1=2, Rf ¼ 0.4) to
give 4 (55%) as pale yellow needles. Mp 48–50ꢁC; IR (film):
3-[(2,4-Dichlorophenoxy)methyl]-1-phenyl-1,5-dihydro-
pyrazol-5-one (5, C16H12N2O2Cl2)
To a stirred solution of compound 2.9 g 4 (10 mmol) in 20cm3
acetic acid, 1.08 cm3 phenyl hydrazine (10 mmol) was added
dropwise within 15 min. After the addition was completed, the
reaction mixture was stirred at room temperature for another
2 h. A solid product precipitated during stirring, it was filtered
off, washed with hot water (20 cm3), dried, and crystallized to
give 5 (75% yield) as pale brown crystals. Mp 179–181ꢁC
(acetic acid); IR (film): ꢂꢀ¼ 1693 (CO), 1599 (C¼N) cmꢀ1; 1H
NMR (270MHz, CDCl3): ꢁ ¼ 3.75 (s, 2H, CH2 pyrazolone),
5.0 (s, 2H, CH2), 7.0–7.90 (m, 8H, Ar–H) ppm; MS: m=z
(%) ¼ 334 [Mþ].
1
ꢂꢀ¼ 1725 (COOEt), 1665 (CO) cmꢀ1; H NMR (270 MHz,
CDCl3): ꢁ ¼ 1.3 (t, 3H, CH3), 3.75 (s, 2H, CH2ꢀ), 4.3 (q, 2H,
CH2-ester), 4.75 (s, 2H, CH2-phenoxy), 6.8 (d, 1H, Ar–H),
7.25 (dd, 1H, Ar–H), 7.45 (d, 1H, Ar–H) ppm; MS: m=z
(%) ¼ 290 [Mþ].
Preparation of compounds 9 and 15. General procedure
A mixture of each 4 or 5 (10 mmol) and 1.19g N,N-dimethyl
formamide dimethyl acetal (10 mmol) in 20 cm3 dry benzene
was refluxed for 3 h. A solid product precipitated after con-
centration, it was filtered off, washed with petroleum ether,
and finally crystallized to afford 9 or 15.
3-[(2,4-Dichlorophenoxy)methyl)]-5-hydroxy-1-phenyl-1H-
pyrazole-4-carbaldehyde (6a, C17H12N2O3Cl2)
Ethyl-4-(2,4-dichlorophenoxy)-2-[(dimethylamino)-
To a solution of 3.35 g 5 (10 mmol) in ethyl formate
(30 cm3), sodium sand (10 mmol) was added (prepared by
refluxing sodium metal in toluene) over a water bath. After
5 min, ethanol (2 drops) was added to the reaction mixture
to activate it and the reflux was continued for 4 h. After a
compact mass was formed, 10 cm3 ethanol were added to
it to get rid of the residual sodium, it was poured over
crushed ice, and finally acidified with HCl. A precipitate
separated out, it was filtered off and crystallized to give
6a (50% yield) as yellow crystal. Mp 218–220ꢁC (etha-
methylene]-3-oxobutanoate (9, C15H17NO4Cl2)
Pale yellow needless, yield (65%), mp 71–73ꢁC (ethanol); IR
(film): ꢂꢀ¼ 1730 (COOEt), 1665 (CO), 1613 (C¼C) cmꢀ1; 1H
NMR (270MHz, DMSO-d6): ꢁ ¼ 1.25 (t, 3H, CH3-ester), 3.4
(s, 6H, N (CH3)2), 4.15 (q, 2H, CH2-ester), 5.15 (s, 2H,
CH2ꢀ), 6.9 (d, 1H, Ar–H), 7.35 (dd, 1H, Ar–H), 7.55 (d, 1H,
Ar–H), 7.90 (s, 1H, ¼CH) ppm; MS: m=z (%) ¼ 345 [Mþ].
3-[(2,4-Dichlorophenoxy)methyl]-4-[(dimethylamino)methy-
lene]-1-phenyl-1,5-dihydropyrazol-5-one (15, C19H17N3O2Cl2)
Pale yellow needless, yield (60%), mp 71–73ꢁC (ethanol);
1
nol); IR (film): ꢂꢀ¼ 3400 (OH), 1630 (CO) cmꢀ1; H NMR
(500 MHz, CDCl3): ꢁ ¼ 5.30 (s, 2H, CH2Oꢀ), 7.27–7.80
(m, 8H, Ar–H), 8.20 (s, 1H, ¼CHOH) ppm; MS: m=z
(%) ¼ 363 [Mþ].
IR (film): ꢂꢀ¼ 1688 (CO), 1600 (C¼N) cmꢀ1
;
1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 2.90 (s, 6H, N(CH3)2), 5.4 (s, 2H,
CH2), 7.13–8.00 (m, 9H, Ar–H, C¼CHN) ppm; MS: m=z
(%) ¼ 389 [Mþ].
5-Chloro-3-[(2,4-dichlorophenoxy)methyl)]-1-phenyl-1H-
pyrazole-4-carbaldehyde (6b, C17H11N2O2Cl3)
Preparation of compounds 10 and 16. General procedure
A mixture of each of compounds 9 or 15 (10 mmol) and 0.69g
hydroxylamine hydrochloride (10 mmol) in 20cm3 acetic acid
was refluxed for 1½h. A solid that precipitated on hot was
filtered off, washed with 20 cm3 water, dried, and finally crys-
tallized to afford 10 or 16.
To 0.73 g dry DMF (10 mmol) cooled to 0ꢁC, 2 cm3
POCl3 (13 mmol) were slowly added at such a rate that
the temperature was maintained below 10ꢁC followed by
the addition of 3.35 g 5 (10 mmol) in small portions. The
resulting solution was stirred at room temperature for
30 min and at 50ꢁC for 1 h. The dark reaction mixture was
then cooled to room temperature and poured slowly onto
ice=H2O and neutralized to pH 6–7 by adding Na2CO3 in
small portions. The resulting brown solid was filtered off,
washed with 50cm3 water, and crystallized to afford 6b
(55% yield) as yellow crystals. Mp 100–102ꢁC (ethanol); IR
Ethyl-3-[(2,4-dichlorophenoxy)methyl]isoxazole-4-
carboxylate (10, C13H11NO4Cl2)
Colorless crystals, yield (70%), mp 55–57ꢁC (DMF);
IR (film): ꢂꢀ¼ 1720 (CO), 1590 (C¼N) cmꢀ1
;
1H NMR
(film): ꢂꢀ¼ 1680 (CHO), 1523 (C¼N) cmꢀ1
;
1H NMR
(500 MHz, DMSO-d6): ꢁ ¼ 1.25 (t, 3H, CH3ꢀ), 4.27 (q, 2H,
CH2-ester), 5.66 (s, 2H, CH2ꢀ), 7.15 (d, 1H, Ar–H), 7.28 (dd,
1H, Ar–H), 7.61 (d, 1H, Ar–H), 9.07 (s, 1H, isoxazole H-5)
ppm; MS: m=z (%) ¼ 315 [Mþ].
(500MHz, DMSO-d6): ꢁ ¼ 5.42 (s, 2H, CH2), 7.36–7.62
(m, 8H, Ar–H), 10.0 (s, 1H, CHO) ppm; MS: m=z (%) ¼
380 [Mþ].

Meldrum’s acid in heterocyclic synthesis
689
lized to give 14 (70% yield) as pale yellow crystals. Mp 200–
201ꢁC (acetic acid); IR (film): ꢂꢀ¼ 1605 (C¼C), 1660 (CO)
cmꢀ1; 1H NMR (500MHz, DMSO-d6): ꢁ ¼ 4.9 (s, 2H, CH2ꢀ),
7.15–7.40 (m, 13H, Ar–H), 7.94 (s, 1H, ¼CH Ph) ppm; MS:
m=z (%) ¼ 422 [Mþ].
5-Azido-3-[(2,4-dichlorophenoxy)methyl)]-1-phenyl-1H-
pyrazole-4-carbaldehyde (7, C17H11N5O2Cl2)
To a solution of 3.8 g 6b (10 mmol) in 25 cm3 DMSO, 0.65 g
sodium azide (10 mmol) were added and the reaction mixture
was stirred for 48h at 35ꢁC in the absence of light. The
solution was diluted with H2O (100 cm3) and extracted with
Et2O (3ꢃ50 cm3). The organic phase was washed with H2O
(100 cm3), after which it was dried (Na2SO4). Removal of
the solvent left a solid residue, which was purified by column
chromatography (silica gel, AcOEt=pet. ether, 1=3, Rf ¼ 0.35)
to give 7 (60% yield) as colorless crystals. Mp 117–118ꢁC; IR
(film): ꢂꢀ¼ 2136 (azido group), 1662 (CO), 1586 (C¼N)
4-[(2-Chloro-4-nitrophenylamino)methylene]-3-[(2,4-
dichlorophenoxy)methyl]-1-phenyl-1,5-dihydropyrazol-5-one
(17, C23H15N4O4Cl3)
A mixture of 3.9g 15 (10 mmol) and 1.72g 2-chloro-4-nitro-
aniline (10 mmol) in 25cm3 acetic acid was refluxed for 3 h. A
precipitate which was formed on hot, filtered off, and crystal-
lized to give 17 (70% yield) as orange crystals. Mp 241–
cmꢀ1
;
1H NMR (500 MHz, DMSO-d6): ꢁ ¼ 5.47 (s, 2H,
243ꢁC (DMF); IR (film): ꢂꢀ¼ 3110 (NH), 1670 (CO) cmꢀ1
;
CH2), 7.41–7.65 (m, 8H, Ar–H), 10.06 (s, 1H, CHO) ppm;
MS: m=z (%) ¼ 388 [Mþ].
1H NMR (500MHz, DMSO-d6): ꢁ ¼ 5.31 (s, 2H, OCH2ꢀ),
7.41–8.48 (m, 11H, Ar–H), 8.49 (s, 1H, ¼CH), 9.05 (s, 1H,
NH) ppm; MS: m=z (%) ¼ 517 [Mþ].
3-[(2,4-Dichlorophenoxy)methyl]-1-phenyl-1H-pyrazole-4-
carbonitrile (8, C17H11N3OCl2)
Compound 7 (3.88 g, 10 mmol) was dissolved in 50cm3
toluene in an atmosphere of dry N2 and stirred at 100ꢁC.
After 5 h, the reaction mixture was cooled to room tempera-
ture, and the toluene was removed in vacuo. The resulting oil
was chromatographed (silica gel, AcOEt=pet.ether, 1=1, Rf ¼
0.25) to afford 8 (55% yield) as a pale yellow crystals. Mp
212–214ꢁC; IR (film): ꢂꢀ¼ 2252 (CN), 1595 (C¼N) cmꢀ1; 1H
NMR (500MHz, DMSO-d6): ꢁ ¼ 5.18 (s, 2H, CH2), 7.48–7.59
(m, 8H, Ar–H), 7.70 (s, 1H, pyrazole H-5) ppm; MS: m=z
(%) ¼ 343 [Mþ].
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3-[(2,4-Dichlorophenoxy)methyl]-4-(hydroxyimino)-1-
phenyl-1,5-dihydropyrazol-5-one (11, C16H11N3O3Cl2)
To a solution of 3.35 g 5 (10 mmol) in 20cm3 acetic acid,
aqueous sodium nitrite (20 mmol) was added portionwise,
with stirring at 0–5ꢁC, over a period of 20 min. After 1½h,
the reaction mixture was poured onto water, a precipitate was
formed, filtered off, and crystallized to give 11 (65% yield) as
orange yellow crystal. Mp 171–173ꢁC (ethanol); IR (film):
ꢂꢀ¼ 3400 (OH), 1650 (CO), 1611 (C¼N) cmꢀ1
9H, 8Ar–H, OH) ppm; MS: m=z (%) ¼ 363 [Mþ].
;
1H NMR
(500 MHz, DMSO-d6): ꢁ ¼ 5.3 (s, 2H, CH2), 7.33–7.73 (m,
3-[(2,4-Dichlorophenoxy)methyl]-4-[benzylidene]-1-phenyl-
1,5-dihydro pyrazole-5-carboxylate (14, C23H16N2O2Cl2)
A mixture of 3.35g 5 (10 mmol) and 2.0 g benzylidene ethyl-
cyanoacetate 12 (10 mmol) in 30cm3 ethanol in presence of
triethylamine (3 drops) was refluxed for 5 h. A precipitate
which was formed on hot, filtered off while hot, and crystal-
11. Pluta K, Andersen KV, Jensen F, Becher J (1988) J Chem
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12. Becher J, Jorgensen PL, Pluta K, Krake NJ, Falt-Hansen
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