Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c]coumarin and pyrazolo[4,3-c]coumarin frameworks

Article abstract of DOI:10.1134/S1068162013040079

Reaction of 4-chlorocoumarin-3-carbonitrile with ethyl thioglycolate and ethyl glycinate hydrochloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the hydrazino derivative which underwent various reactions to build new heterocyclic rings containing thienocoumarin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent nucleophilic substitution reactions with various amines. The following treatment with formaldehyde under Mannich conditions afforded the corresponding imidazo derivatives. Reaction of chloroacetylamino with potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile precursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbonitrile with hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substituted pyrimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethylaminotriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable antifungal and antibacterial activity in the in vitro test systems.

Full text of DOI:10.1134/S1068162013040079

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2013, Vol. 39, No. 5, pp. 553–564. © Pleiades Publishing, Ltd., 2013.
Synthesis and Antimicrobial Activity of New Heterocyclic
Compounds Containing Thieno[3,2ꢀc]coumarin
and Pyrazolo[4,3ꢀc
]coumarin Frameworks1
Adel M. Kamal ElꢀDean, Remon M. Zaki2, Ahmed A. Geies,
Shaban M. Radwan, and Mahmoud S. Tolba
Chemistry department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Received November 21, 2012; in final form, February 26, 2013
Abstract—Reaction of 4ꢀchlorocoumarinꢀ3ꢀcarbonitrile with ethyl thioglycolate and ethyl glycinate hydroꢀ
chloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the
hydrazino derivative which underwent various reactions to build new heterocyclic rings containing thienocouꢀ
marin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent
nucleophilic substitution reactions with various amines. The following treatment with formaldehyde under
Mannich conditions afforded the corresponding imidazo derivatives. Reaction of chloroacetylamino with
potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile preꢀ
cursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbonitrile with
hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substiꢀ
tuted pyrimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethyꢀ
laminotriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable
antifungal and antibacterial activity in the in vitro test systems.
Keywords: thienocoumarine, pyrazolocoumarine, pyrimidothienocoumarine, imidazo thienocoumarine, syntheꢀ
sis, antiꢀmicrobial activity
DOI: 10.1134/S1068162013040079
2 1
INTRODUCTION
RESULTS AND DISCUSSION
Reaction of 4ꢀhydroxycoumarin
Coumarins contain the parent nucleus of benzo(ꢀ
(
I
)
with
pyrone) and occur in plants of Orchidaceae and Leguꢀ
minaceae families [1]. Naturally occurring and synꢀ
thetic coumarins display important pharmacological
properties, such as antitumor [2], anticonvulsant [3],
antiꢀinflammatory [4, 10], antiꢀHIV [5], anticoaguꢀ
lant [6], antibacterial [7] and antioxidant [8, 9] activiꢀ
ties. Among the diverse activities of coumarin the
effect against breast cancer seems to draw special
HCONMe2: POCl3 mixture in chloroform under Vilsꢀ
meier–Haack reaction conditions afforded chloroꢀ
coumarin carboxaldehyde (II) [15]. Aldehyde (II) was
condensed with hydroxylꢀamine hydrochloride in
refluxing ethanol in the presence of fused sodium aceꢀ
tate to give the corresponding oxime (III). The latter
compound was dehydrated using POCl3 to afford
attention [11–13]. Coumarins are also used to prepare 4ꢀchloroꢀ2Hꢀcoumarinꢀ3ꢀcarbonitrile (IV) (Scheme 1).
other chemicals, in particular rodent poisons, such as
warfarin or insecticides such as hymecromone. Their
antiꢀinflammatory properties are usually associated
with the capability of modulating the inflammatory
cells [14].
OH
Cl
CHO
O
POCl
3
DMF/CHCl
3
O
O
O
(II)
The main representatives of the class are the
hydroxyl derivatives, 4ꢀ and 7ꢀhydroxy coumarins,
also biologically active and very important for the synꢀ
thesis of other coumarin derivatives. Bearing in mind
the above benefits of coumarin derivatives, in this work
we aimed to build a heterocyclic ring on coumarin
starting from the commercially available 4ꢀhydroxyꢀ
coumarin and hoping that the new products described
below are biologically useful.
(I)
NH OH ⋅ HCl/AcONa
2
EtOH
Cl
Cl
O
N
POCl
3
–H O
N
H
2
O
O
O
O
1
(IV)
(III)
The article is published in the original.
Corresponding author: eꢀmail: remonch2003@yahoo.com.
2
Scheme 1.
553

554
KAMAL ELꢀDEAN et al.
Chlorocarbonitrile (IV) was reacted with ethyl reacted with ethyl glycinate hydrochloride in DMF
thioglycolate in ethanolic sodium ethoxide to afford in the presence of K2CO3 to afford glycinate derivaꢀ
ethyl aminothienocoumarincarboxylate ( ). Reaction tive (VII), which cyclized in ethanolic sodium ethoxꢀ
of amino ester ( ) with hydrazine under neat condiꢀ ide solution to ethyl 3ꢀaminoꢀ4ꢀoxoꢀ1,4ꢀdihydroꢀ
tions afforded the corresponding carbohydrazide (VI). chromeno[4,3ꢀb]pyrroleꢀ2ꢀcarboxylate VIII
V
V
(
)
On the other hand, chlorocarbonitrile (V) was (Scheme 2).
CO2CH2CH3
NH2
Cl
S
N
HSCH CO Et
2
2
EtOH/EtONa
O
(IV)
O
O
(V)
O
HClH NCH CO Et
NH NH
2
EtOH
⋅
H O
2
2
DMF/K CO /70°C
2
2
2
2
3
CONHNH2
NHCH2CO2Et
N
S
NH2
O
(VII)
O
O
(VI)
O
EtOH/EtONa
CO2CH2CH3
NH2
HN
O
O
(VIII)
Scheme 2.
Thienochromenecarbohydrazide (VI) was considꢀ ment upon boiling in an inert solvent (dry xylene) to
ered as precursor of other heterocyclic compounds.
Condensation of carbohydrazide (VI) with acetyl aceꢀ
tone in ethanol afforded pyrazolyl derivative (IX).
Condensation of carbohydrazide (VI) with aromatic
afford imidazothienocoumarine (XIV) (Scheme 3).
Aminothienochromene ( ) was reacted with chloꢀ
V
roacetyl chloride in dioxane at 70°C to afford the corꢀ
responding chloroacetyl amino derivative (XV). The
latter underwent nucleophilic substitution reaction
with aromatic amines to give arylaminoacetyl derivaꢀ
aldehyde to gave the corresponding hydrazone (X).
Which was cyclized using triethyl orthoformate in ethꢀ
anol in the presence of catalytic drops of acetic acid to
give pyrimidothienochromene (XI). Carbohydrazide
tives (XVIa–f). Treatment of compounds (XVIa,b
)
with formaldehyde under Mannich conditions
afforded 1,3–diaminourea compounds (XVIIa,b).
Reaction of chloroacetyl derivative (XV) with potasꢀ
sium thiocyanate in ethanol lead to pyrimidothienolꢀ
coumarinysulfanylacetate (XVIII) in one step [16]
(
VI) was also reacted with triethyl orthoformate in
ethanol in the presence of catalytic drops of acetic acid
to give pyrimidothienocoumarine (XII). Also, carboꢀ
hydrazide (VI) was converted to the corresponding
carboazide (XIII) using sodium nitrite solution in aceꢀ
tic acid. The product underwent Curtius rearrangeꢀ (Scheme 4).
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY
555
O
N
OEt
N
N
S
CH(OEt) /EtOH/AcOH
3
O
O
(XII)
O
O
O
N3
N
S
N
S
Ac (CH )
2
NaNO /AcOH
2
2
NH2
(VI)
NH2
O
(XIII)
O
(IX)
O
S
Ar
ArCHO
N
O
O
N
Ar
Dry Xylene
N
N
N
H
H
O
N
S
S
NH2
N
CH(OEt) /EtOH
3
H
AcOH
O
(XI)
O
O
(X)
O
O
(XIV)
O
Scheme 3.
CO2Et
O
N
S
NH2
O
S
NH
S
OEt
O
(V)
O
O
O
(XVIII)
ClCOCH Cl/dioxane
2
KSCN/EtOH
CO2Et
O
S
Cl
O
N
CO2Et
O
ArNH /EtOH
2
R1
O
O
S
O
O
S
HCHO/AcOH
EtOH
(XV)
N
N
R2
N
N
O
O
O
O
(XVI)
XVIa, R1 = Ph, R2 = H
(XVIIa,b)
R
XVIb, R1 = C6H4CH3ꢀp, R2 = H
XVIc, R1, R2 = piperidinyl
XVId, R1, R2 = morpholinyl
XVIe, R1, R2 = piperazinyl
XVIIa R = H
XVIIb R = CH3
XVIf, R1 = C6H4SO2NH2ꢀp, R2 = H
XVIg, R1 = C6H4SO2NHꢀdiazineꢀp, R2 = H
Scheme 4.
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556
KAMAL ELꢀDEAN et al.
CO2Et
O
S
S
N
H
CN
CO2Et
O
S
O
O
Cl
KSCN
N
H
O
O
O
OEt
NH
S
N
S
O
O
O
O
N
S
NH
OEt
S
O
O
O
(XVIII)
Scheme 5.
The putative intermediates on the route to pyrimiꢀ carboxylate (XXIX). In this case the pyrazole NH
dothienocoumarin (XVIII), are showen in Scheme 5. acted as a nucleophile and attack carbonitrile
group.That step was followed by tautomerisation,
rather than loss of ethanol molecule which would afford
oxopyrimidocoumarine carbonitrile (XXX). Diazotizaꢀ
tion of amino group in compound (XXII) with sodium
The ethyl thioacetate compound ester (XVIII) was
used as versatile precursor for synthesis of other
pyrimidothienocoumarine derivatives
(XIX–XXI).
Hydrazinolysis of ester (XVIII) with hydrazine under
neat conditions afforded the corresponding carbohyꢀ
drizde derivative (XIX). Reaction of carbohydrazide
XIX) with acetyl acetone in ethanol gave the dimethꢀ
ylpyrazolyl derivative (XX), while reaction with bezalꢀ
nitrite solution in conc HCl afforded the diazonium salt
(XXXI) which was coupled (in situ) with ethyl cyanoaceꢀ
tate and ethyl acetoacetate in presence of sodiumacetat
giving rise to ethylaminotriazinooyrazolocoumarineꢀ
carboxylate (XXXII) andethylbutanoate compounds
(
dehyde in presence of piperidine as a basic catalyst
(XXXIII) respectively (Scheme 8).
afforded the corresponding Schiff’s base (XXI
)
Chemical structure and homogeneity of all products
obtained was confirmed by IR and NMR spectroscopy,
massꢀspectrometry and elemental microanalysis.
(Scheme 6).
Reaction of chlorocoumarinecarbonitrile (IV) with
hydrazine in ethanol afforded the aminopyrazolocouꢀ
marine (XXII) which was used as a starting material for
synthesis of other heterocyclic compounds. Thus,
condensation of (XXII) with bifunctional compounds
namely: acetyl acetone, ethyl cyanoacetate, diethyl
malonate, ethyl acetoacetate and ethyl benzoylacetate
in acetic acid afforded the corresponding pyrimido
derivatives (XXIII)–(XXIV) (Scheme 7).
Biological Activities
Some of the synthesized compounds in this work
screened in vitro for their antimicrobial activity
against some strains of bacteria and fungi by technique
described in [17]. 2% concentration of selected comꢀ
pounds in DMSO was used in all cases. The inhibition
zone (mm) compared with clortrimazole as a referꢀ
ence.in the case of antifungal tests and with chloramꢀ
phenicol in case of antibacterial tests.
Reaction of aminopyrazolocoumarine (XXII
with ethylꢀ2ꢀcyanoꢀ3ꢀethoxyacrylate afforded
ethylcyanodihydropyrazolocoumarinylaminoacrylate
XXVIII). Refluxing ethyl acrylate ester with acetic
)
(
Some tested compounds showed remarkable antiꢀ
acid yielded ethylaminopyrimidopyrazolocoumarine bacterial and anti fungal activities. In case of antiꢀfunꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY
557
O
NH
N
N
S
S
N
O
O
O
(XX)
(CH CO) CH /EtOH
2
3
2
O
N
O
N
S
NH
S
NH
H
O
H NNH
2
neat
N
2
S
S
NH2
O
O
O
O
O
(XIX)
O
(XVIII)
PhCHO/piperidine
EtOH
O
S
NH
H
N
N
S
N
Ph
O
O
O
(XXI)
Scheme 6.
O
N
N
O
N
H
O
O
Cl
O
(XXV)
N
N
CN
O
N
CH (CO Et)
2
2
2
AcOH
(CH CO) CH
2
3
AcOH
2
O
O
(IV)
H NNH /EtOH
2
(XXIII)
2
HN
N
O
NH2
NCCH CO Et
2
PhCOCH CO Et
2
O
(XXII)
2
AcOH
2
AcOH
NH2
Ph
N
O
N
O
CH COCH CO Et
2
3
AcOH
2
N
N
O
N
H
O
O
N
H
O
N
N
O
O
(XXIV)
(XXVII)
N
H
O
(XXVI)
Scheme 7.
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558
KAMAL ELꢀDEAN et al.
CN
H
N
EtOCH
C
HN
O
N
O
HN
N
O
N
CO Et
CO2Et
2
+
N
−
i) NaNO /HCl
2
N
Cl
NH
N
H
CN
2
O
O
O
(XXVIII)
(XXII)
(XXXI)
ii) CH3COCH2CO2Et/CH3CO2Na
EtOH
ii) NCCH2CO2Et/CH3CO2Na
EtOH
AcOH
H
NH
2
N
O
N
N
COOEt
COCH
N
O
N
O
3
N
H
N
N
O
COOEt
NH
N
O
2
(XXXIII)
CN
COOEt
N
O
N
N
N
(XXXII)
N
H
O
O
O
(XXIX)
(XXX)
Scheme 8.
gal activity (Table 1) aminothienocoumarinecarboxyꢀ
(
XVIa) shows high activity, comparable to that of (VI
and (VII). Replacement of the thieno ring in comꢀ
pound ( ) by pyrazole ring leads to active derivative
XXXII); compound (XXIV) is active only against
Candida albicans and Geotrichum candidum
As for the antibacterial activity, compounds (XVIa
XVIb XVIe and XXXII) showed no antiꢀbacterial
activity against all bacterial species (Table 2).
XVIg). Somewhat unexpectedly compound Almost all of the remaining samples were active
)
late ( ) is effective only Candida albicans and Scopuꢀ
V
V
lariopsis, while replacement of the ester group with
carbohydrazide group in compound (VI) considerably
broadens the spectrum of activity and leads to highly
active product. The glycinate derivative (VII) is also
quite active. The cyclized compound (VIII) shows low
(
.
,
,
activity, as well as compounds (XV, XVIb, XVId, XVIe,
XVIf
,
Table 1. Antifungal activity (inhibtion zone, mm)
Candida
albicans
Trichphyton
rubrum
Aspergillus
flavus
Fusarium
oxysporum
Scopulariopsis
brevicaulis
Geotrichum
candidum
Compd.
(V)
13
14
9
0
0
0
0
16
9
8
13
10
0
0
13
0
(VI)
10
(VII)
10
0
0
(VIII)
12
10
13
13
0
0
0
12
0
(XV)
0
0
0
0
(XVIa)
10
0
12, p.i.
0
10
0
11
8
(XVIb)
0
0
0
(XVId)
0
0
0
0
(XVIe)
0
0
0
0
0
0
(XVIf)
0
0
0
0
0
10
0
(XVIg)
13
10
14
20
0
0
0
0
(XXIV)
(XXXII)
Clotrimazole
p.i., partial inhibition.
0
0
0
0
8
12, pi
36
9
9
10
20
12
24
44
28
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY
Table 2. Antibacterial activity (inhibtion zone, mm)
559
Serratia
marcescens
(–ve)
Staphlococcus
aureus (+ve)
Bacillus
cereus (+ve)
Escherichia
coli (–ve)
Pseudomonas
aeruginos (–ve)
Micrococcus
luteus (+ve)
Compd.
(V)
9
10
8
0
0
0
0
10
10
8
8
11
0
8
0
(VI)
(VII)
9
0
8
(VIII)
10
8
0
10
0
0
0
0
(XV)
0
0
0
0
(XVIa)
(XVIb)
(XVId)
(XVIe)
(XVIf)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
9
0
0
0
0
0
0
0
0
9
0
0
11
0
12
0
0
(XVIg)
(XXIV)
(XXXII)
Chloramphenicol
10
10
0
0
9
0
0
9
9
0
0
0
0
0
0
0
18
22
18
18
20
20
against Staphylococcus aureus. Other bacterial strains (CDCl3):
δ
1.30–1.45 (3H,
= 6.0 Hz, q, CH2)
7.20–7.80 (4H, m, ArH). Mass:
288.70 [
+ – 1]. Found: C, 58.23; H, 3.96; N, 4.78; S,
11.15%. Calculated: C14H11NO4S (289.31): C, 58.12;
H, 3.83; N, 4.84; S, 11.08%.
J
= 7.0 Hz, t, CH3), 4.30–
6.90 (2H, s, NH2)
: 289.71 [
+],
4.50 (2H,
J
,
,
were selectively susseptible to the action of tested
derivatives. For example, the aminothieno coumarinꢀ
m/
z
M
M
ecarboxylate (
remarkable activity especially against Pseudomonas
aeruginosa
V) and carbohydrazide (VI) exhibited
.
3ꢀAminoꢀ4ꢀoxoꢀ4 ꢀthieno[3,2ꢀ
H
c
]chromeneꢀ2ꢀcarboꢀ
hydrazide (VI). A mixture of amino ester (
V) (2 g,
EXPERIMENTAL
7 mmol) and hydrazine 99% (3 mL, 0.06 mol) was
fused for 1 h then absolute ethanol (7 mL) was added
dropwise. The reaction mixture was refluxed for addiꢀ
tional two h. The solid product formed on hot during
reflux was recrystallized from ethanol to give pale yelꢀ
low crystals in 76% yield, m.p. 280–282°C. IR: 3470,
3300, 3180 (NH, NH2), 3050 (CH aromatic), 2900,
2870 (CH aliphatic), 1725 (C=O chromene), 1630
All melting points are uncorrected and measured
on a Fisher–John apparatus. Elemental analyses were
determined on an Elementar Analysensystem GmbH
VarioEL V.3 microanalyzer in the central lab of Assiut
University. Their results were found to be in good
agreement ( 0.2%) with the calculated values. IR
spectra were recorded on a Pye–Unicam Spꢀ100 specꢀ
trophotometer using KBr wafer technique. NMR
spectra were recorded on a varian EMꢀ390 90 MHz
and Joel 400 MHz spectrometers in a suitable
deutrated solvent using TMS as internal standard
(chemical shifts in ppm). MS spectra were recorded
(CONH). 1H NMR (DMSOꢀ
2NH2), 6.90–7.60 (4H, 2s, 2NH2), 6.90–7.60 (4H,
m, ArH), 7.85 (1H, s, NH). Mass: 274.6 [
+],
243.19 [
+– 31]. Found: C, 52.30; H, 3.35; N, 15.15;
S, 11.75%. Calculated: C12H9N3O3S (275.29): C,
52.36; H, 3.30; N, 15.26; S, 11.65%.
d6): δ 4.40, 4.70 (4H, 2s,
m/z
M
M
on Jeol JMSꢀ600 apparatus. Compounds (I) and (IV)
were prepared according to literature procedure [15]
with melting points 120–122°C, 190–192°C, 152–
154°C respectively.
(3ꢀCyanoꢀ2ꢀoxoꢀ2 ꢀchromenꢀ4ꢀylamino)ꢀacetic acid
ethyl ester (VII). A mixture of 4ꢀchloroꢀ2ꢀoxoꢀ2
chromeneꢀ3ꢀcarbonitrile (IV) (0.88 g, 4.3 mmol) and
H
Hꢀ
Ethyl 3ꢀaminoꢀ4ꢀoxoꢀ4
2ꢀcarboxylate (V). A mixture of chloro compound heated on steam bath in presence of anhydrous potasꢀ
IV) (4.9 g, 0.024 mol) and ethyl thioglycolate (3 mL, sium carbonate (0.5 g, 3.6 mmol) for 4 h to afford a
0.025 mol) was stirred in absolute ethanol (20 mL) in brown precipitate which was recrystallized from ethaꢀ
presence of sodium ethoxide (1 mL, 0.1 mol) for 1 h. nol as brown crystals in 50% yield, m.p. 198–200°C
The solid product formed was collected, dried and IR: 3300 (NH), 3100 (CH aromatic), 2900, 2850 (CH
recrystallized from ethanol as a yellow precipitate in aliphatic), 2150 (CN), 1720 (C=O chromene), 1700
88% yield, m.p. 208–210°C; IR: 3480, 3350 (NH2), (C=O ester). 1H NMR (DMSOꢀ
6): 1.20–1.35 (3H
3030 (CH aromatic), 2900, 2850 (CH aliphatic), 1725 t, CH3), 3.80 (2H, s, CH2), 4.15–4.40 (2H, q, CH2),
Hꢀthieno[3,2ꢀc]chromeneꢀ ethyl glycinate hydrochloride in DMF (10 mL) was
(
.
d
δ
,
1
(C=O chromene), 1695 (C=O ester) cm–1. H NMR 7.30–7.80 (4H, m, ArH)
, 10.30 (1H, s, NH). Found:
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KAMAL ELꢀDEAN et al.
1
C, 61.70; H, 4.60; N, 10.10%. Calculated: 1610 (CO). H NMR (CF3CO2D)
δ
: 7.50–7.90 (9H
,
C14H12N2O4 (272.26): C, 61.76; H, 4.44; N, 10.29%.
m, ArH), 8.20 (1H, s, CH pyrimidine) 9.80 (1H, s,
,
CH=N). Found: C, 64.25; H, 2.85; N, 11.38; S,
8.46%. Calculated: C20H11N3O3S (373.39): C, 64.34;
H, 2.97; N, 11.25; S, 8.59%.
Ethyl 3ꢀaminoꢀ4ꢀoxoꢀ1,4ꢀdihydrochromeno[4,3ꢀ
b
]pyrroleꢀ2ꢀcarboxylate (VIII). A solution of ethyl
amino acetate ester (VII) (0.27 g, 1 mmol) in DMF
(10 mL) was heated on steam bath in presence of
anhydrous potassium carbonate (0.3 g, 2.17 mmol) for no[3,2ꢀ
10 h. The solid precipitate which formed on cooling mixture of 3ꢀaminoꢀ4ꢀoxoꢀ
Ethyl (6,10ꢀdioxoꢀ6
]pyrimidinꢀ9(10
H
ꢀchromeno[3',4':4,5]thieꢀ
)ꢀyl)imidoꢀformate (XII)
Hꢀthieno[3,2ꢀ ]chroꢀ
d
H
. A
4
c
and diluted with water was filtered off, dried and meneꢀ2ꢀcarbohydrazide (VI) (2 g, 0.01 mol) and triꢀ
recrystallized from ethanol as pale brown crystals in ethyl orthoformate (4 mL, 0.027 mol) was refluxed in
53%, m.p.: 260–264°C; IR: 3300, 3250, 3150 (NH + presence of glacial acetic acid (1 mL) for 1 h. A white
NH2), 3030 (CH aromatic), 2900, 2850 (CH aliꢀ precipitate was formed on hot during reflux. The solid
phatic), 1720 (C=O chromene), 1690 (C=O unsaturꢀ product filtered off, dried and recrystallized from ethꢀ
1
ated ester). H NMR (DMSOꢀ
d
6):
δ
1.35–1.50 (3H, anolꢀdioxane mixture as white crystals in 75% yield,
= 7.5 Hz, q, m.p. 318–320°C. IR: 3030 (CH aromatic), 2910,
6.20 (2H, s, NH2), 7.30–7.80 (4H, m, ArH), 2850 (CH aliphatic), 1740 (C=O chromene), 1675
J
= 9.0 Hz, t, CH3), 4.20–4.40 (2H,
CH2)
10.10 (1H, s, NH). Mass: m/z 273.15 [
272.10 [M+
. Found: C, 61.80; H, 4.52; N, 10.35%. 1.40 (3H, t, CH3), 4.35–4.50 (2H, q, CH2), 7.60–8.30
Calculated: C14H12N2O4 (272.26): C, 61.76; H, 4.44; 4H, m, ArH), 9.80 (1H, s, CH=N), 10.20 (1H, s, CH
N, 10.29%. pyrimidine). Mass: m/z 340.13 [
+– 1], 338.76 [M+
3ꢀAminoꢀ2ꢀ[(3,5ꢀdimethylꢀ1
nyl]ꢀ4 ꢀthieno[3,2ꢀ ]chromenꢀ4ꢀone (IX). A mixture
of carbohydrazide (VI) (1 g, 3.6 mmol) and acetyl aceꢀ
tone (0.4 mL, 4 mmol) was refluxed in ethanol
(10 mL) for 4 h. The yellow precipitate was filtered off bonylazide (XIII). To a Stirred a solution of 3ꢀaminoꢀ4ꢀ
and recrystallized from ethanol as yellow crystals in oxoꢀ Hꢀthieno[3,2ꢀ ]chromeneꢀ2ꢀcarbohydrazide (VI
J
,
1
M
++ 1], (C=O pyrimidine). H NMR (CF3CO2D):
δ 1.25–
]
(
M
–
2]. Found: C, 56.42; H, 3.18; N, 12.26; S, 9.43%. Calꢀ
culated: C16H11N3O4S (341.35): C, 56.30; H, 3.25; N,
12.31; S, 9.39%.
H
ꢀpyrazolꢀ1ꢀyl)carboꢀ
H
c
3ꢀAminoꢀ4ꢀoxoꢀ4Hꢀthieno[3,2ꢀc]chromeneꢀ2ꢀcarꢀ
4
c
)
77% yield, m.p. 216–218°C. IR: 3450, 3350 (NH2), (0.5 g, 1.80 mmol) in of glacial acetic acid (15 mL)
3050 (CH aromatic), 2930 (CH aliphatic), 1700 then adding sodium nitrite solution (0.5 g, 7.25 mmol,
(C=O chromene), 1680 (C=O). 1H NMR 10%) was added drop wise at 0°C for 1/2 h a dark
(
CF3CO2D):
2s, 2CH3), 6.00 (1H, s, CH pyrazole), 7.10–7.60 (4H, tered off, washed with water, dried and used without
m, ArH. Mass: . Found: C, 60.20; H, recrystallization for the following step, in 47% yield,
338.89 [M+
3.75; N, 12.45; S, 9.54%. Calculated: C17H13N3O3S m.p. 160–162°C. IR: 3450, 3350 (NH2), 2950, 2850
(339.38): C, 60.17; H, 3.86; N, 12.38; S, 9.45%. (CH aliphatic), 2100 (N3), 1720 (C=O chromene),
1665 (C=O azide). 1H NMR (DMSOꢀ
6): 6.55 (2H
δ
2.40–2.60 (6H, 2s, 2CH3), 6.00 (1H
,
brown precipitate is formed. The product formed filꢀ
m/z
]
d
δ
,
3ꢀAminoꢀ4ꢀoxoꢀ 'ꢀ[(1 )ꢀphenylmethylene]ꢀ4Hꢀ
N
E
s, NH2), 7.20–7.60 (4H, m, ArH). Found: C, 50.39;
H, 2.07; N, 19.52; S, 11.26%. Calculated:
C12H6N4O3S (286.27): C, 50.35; H, 2.11; N, 19.57; S,
11.20%.
thieno[3,2ꢀ ]chromeneꢀ2ꢀcarbo hydrazide (X) A mixꢀ
ture of carbohydrazide ( ) (0.5 g, 1.82 mmol) and
c
.
V
benzaldehyde (1 mL, 10 mmol) in ethanol (10 mL)
was refluxed for 3 h. in presence of few drops of piperꢀ
diene (0.5 mL) as a catalyst. The solid product formed
on hot during reflux was collected and recrystalized
Rearrangement of 3ꢀaminoꢀ4ꢀoxoꢀ4
]chromeneꢀ2ꢀcarbonylazide (XIII): Formation of 7,9ꢀ
,8 ꢀchromeno[3',4':4,5]thieno[2,3ꢀ ]imiꢀ
165–167°C; IR: 3580, 4470, 3380 (NH, NH2), 1670 dazoleꢀ6,8ꢀdione (XIV). ꢀAminoꢀ4ꢀoxoꢀ
(C=O amide), 1618 (C=N), 1720 (C=O chromene). thieno[3,2ꢀ ]chromeneꢀ2ꢀcarbonylazide (XIII) (1 g,
1H NMR (CF3CO2D):
.70–7.90 (m, ArH). Found: 3.5 mmol) in dry xylene (10 mL) was refluxed for
C, 62.73; H, 3.54; N, 11.48; S, 8.65%. Calculated: ½ h. The solid product which formed on hot was filꢀ
C19H13N3O3S (363.40): C, 62.80; H, 3.61; N, 11.56; S, tered off, washed several times with xylene, dried and
Hꢀthieno[3,2ꢀ
c
from dioxane to give yellow crystals in 60% yield, m.p. dihydroꢀ6
H
H
d
3
4Hꢀ
c
δ
7
1
8.82%.
9ꢀ{[(1
[3',4':4,5]thieno[3,2ꢀ
Amixture of 3ꢀaminoꢀ4ꢀoxoꢀ
ene]ꢀ4 ꢀthieno[3,2ꢀ ]chromeneꢀ2ꢀcarbohydrazide (X)
(0.25 g, 0.60 mmol) and triethyl orthoformate (2 mL,
0.014 mol) was refluxed in ethanol (10 mL) and a few
drops of glacial acetic acid (0.3 mL) was added and the
mixture refluxed for 3 h. The solid product which
recrystallized from xylene as dark green crystals in
60% yield, m.p. 345–347°C. IR: 3450, 3250 (2NH),
3050 (CH aliphatic), 2950–2860 (CH aliphatic), 1720
E
)ꢀPhenylmethylene]amino}ꢀ6
]pyrimidineꢀ6,10(9
'ꢀ[(1 )ꢀphenylmethylꢀ
H
ꢀchromenoꢀ
d
H)ꢀdione (XI)
1
(C=O chromene), 1630 (C=O imidazole). H NMR
N
E
(CF3CO2D): δ 7.20–7.70 (m, ArH). Found: C, 55.88;
H
c
H, 2.30; N, 10.81; S, 12.50%. Calculated: C12H6O3N2S
(258.26): C, 55.81; H, 2.34; N, 10.85; S, 12.42%.
Ethyl 3ꢀ[(chloroacetyl)amino]ꢀ4ꢀoxoꢀ4 ꢀthieno[3,2ꢀ
]chromeneꢀ2ꢀcarboxylate (XV) Carbohydrazide (
H
c
V)
formed on hot during reflux filtered off, dried and (4 g, 13.84 mmol) and (4 g, 35.4 mmol) of chloro
recrystallized from dioxane as yellow precipitate in acetyl choride were heated under neat conditions on
80% yield, m.p. 298–300°C. IR: 3150 (CH aromatic), water bath at 70°C for 2 h, the mixture then was
2900–2850 (CH aliphatic), 1710 (C=O chromene), allowed to cool and poured into cold water (100 mL),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 5
2013

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
561
then the mixture was neutralized with sodium carbonꢀ lated: C21H22N2O5S (414.48): C, 60.85; H, 5.35; N,
ate solution (10%) till just alkaline. The solid product 6.76; S, 7.74%.
was collected and recrystallized from ethanol as white
crystals in 77.5% yield, m.p. 155–158°C. IR: 3350
(NH), 3000 (CH aromatic), 2950 (CH aliphatic),
Ethyl
3ꢀ[(morpholinꢀ4ꢀylacetyl)amino]ꢀ4ꢀoxoꢀ
]chromeneꢀ2ꢀcarboxylate (XVId).
4
H
ꢀthieno[3,2ꢀ
c
Obtained as the above procedure by the reaction with
morpholine for 5 min. as pale yellow needles in 80%
yield, m.p. 265–266°C. IR: 3300 (NH), 2990 (CH
aromatic), 2850 (CH aliphatic), 1610 (CO amide),
1720 (C=O chromene), 1700 (unsat. ester), 1680 (CO
1
amide) cm–1. H NMR (DMSOꢀ
d6):
δ
1.35–1.50
(3H,
2H,
J
= 8.5 Hz t, CH3), 3.50 (2H, s, CH2), 4.30–4.50
= 7.0 Hz, q, CH2), 7.40–8.30 (4H, m, ArH),
1690 (C=O unsat ester). 1H NMR (DMSOꢀ
d
6):
= 7.5 Hz t, CH3), 4.20–4.35 (2H,
= 6.0 Hz, q, CH2) 3.80 (2H, s, CH2) 3.25 (4H, s,
CH2–O) 2.80 (4H, s, 2CH2–N), 7.20–7.80 (4H, m,
(
J
10.40 (1H, s, NH). Found: C, 52.60; H, 3.28; Cl, 9.74;
N, 3.78; S, 8.80%. Calculated: C16H12ClNO5S
(365.79) C, 52.54; H, 3.31; Cl, 9.69; N, 3.83; S,
8.77%.
δ
J
1.10–1.50 (3H, J
,
,
,
ArH), 10.70 (1H, s, NH). Found: C, 57.73; H, 4.82;
N, 6.75; S, 7.77%. Calculated: C20H20N2O6S (416.46):
C, 57.68; H, 4.84; N, 6.73; S, 7.70%.
Ethyl 4ꢀoxoꢀ3ꢀ[(piperazinꢀ1ꢀylacetyl)amino]ꢀ4
thieno[3,2ꢀ ]chromeneꢀ2ꢀcarboxylate (XVIe) A mixture
Ethyl 4ꢀoxoꢀ3ꢀ[(
N
ꢀalkyl(aryl)glycyl)amino]ꢀ4
Hꢀ
thieno[3,2ꢀ ]chromeneꢀ2ꢀcarboxylate
c
(XVIa–d).
Hꢀ
General procedure. A mixture of chloro acetamide
compound (XV) (1 g, 2.74 mmol) and the correspondꢀ
ing primaryor secondary amine (2.74 mmol) was
refluxed in ethanol (20 mL) for 2 h. The solid product
which formed on cooling filtered off, dried and recrysꢀ
tallized from ethanol.
c
.
of chloro acetamide derivative (XV) (0.5 g, 1.37 mmol)
and piperazine (0.15 g,1.74 mmol) was refluxed in ethꢀ
anol (10 mL) in presence triethylamine (0.5 mL) for
4 h. The solid product was collected, recrystallized
from ethanol as yellow crystals in 80% yield,
m.p.: 268–270°C. IR: 3250 (NH), 3050 (CH aroꢀ
matic), 2900–2850 (CH aliphatic), 1680 (CO amide).
Ethyl
thieno[3,2ꢀ
4ꢀoxoꢀ3ꢀ[(
N
ꢀphenylglycyl)amino]ꢀ4
Hꢀ
c
]chromeneꢀ2ꢀcarboxylate (XVIa)
.
Obtained
as the above procedure by the reaction with aniline as
white crystals in 69% yield, m.p.: 234–236°C. IR:
3380, 3250 (2NH), 3050 (CH aromatic), 2950 (CH
aliphatic), 1720 (C=O chromene), 1695 (CO ester),
1H NMR (DMSOꢀd6
t, CH3), 2.50 (4H, m, 2CH2)
3.20 (2H, s, CH2CO), 4.35–4.50 (2H,
CH2), 6.80 (1H, s, NH piperazine), 7.20–7.70 (4H
)
δ
: 1.00–1.25 (3H,
2.70 (4H, m, 2CH2)
= 7.5 Hz, q,
J = 9.5 Hz,
,
,
J
,
1660 (C=O amide). 1H NMR (DMSOꢀ
d
6):
= 7.5 Hz, t, CH3), 4.00 (2H, s, CH2), 4.30–
4.60 (2H, = 6.5 Hz, q, CH2), 6.80 (1H, t, NHPh)
7.20–7.80 (9H, m, ArH), 10.30 (1H, s, NHCO)
δ 1.35–1.55
m, ArH), 10.10 (1H, s, NHCO). Found: C, 57.79; H,
5.13; N, 10.07; S, 7.80%. Calculated: C20H21N3O5S
(415.47): C, 57.82; H, 5.09; N, 10.11, S, 7.72%.
Ethylꢀ3ꢀ(2ꢀ(4ꢀsulfamoylphenylamino)acetamido)ꢀ
(3H,
J
J
,
.
Found: C, 62.49; H, 4.20; N, 6.66; S, 7.67%. Calcuꢀ
lated: C22H18N2O5S (422.46): C, 62.55; H, 4.29; N,
6.63; S, 7.59%.
4ꢀoxoꢀ4
A mixture of ethyl 3ꢀ[(chloroacetyl)amino]ꢀ4ꢀoxoꢀ
ꢀthieno[3,2ꢀ ]chromeneꢀ2ꢀcarboxylate (XV) (0.5 g,
Hꢀthieno[3,2ꢀc]chromeneꢀ2ꢀcarboxylate (XVIf).
4H
c
Ethylꢀ3ꢀ[
ꢀthieno[3,2ꢀ
Obtained as the above procedure by the reaction of
XV) with ꢀtoluidine as white needles in 81.50%
yield, m.p. 240–242°C. IR: 3460, 3350 (2NH), 1725
(C=O chromene), 1665 (CO amide). 1H NMR
DMSOꢀ 6): 1.25–1.40 (3H, = 8.0 Hz, t, CH3),
2.20 (3H, s, CH3 ꢀtoluidine) 3.90 (2H, s, CH2CO)
4.10–4.25 (2H, q, = 6.5 Hz, CH2), 6.60 (1H, s, NHꢀ
Ph), 7.20–7.80 (8H, m, ArH), 10.30 (1H, s, CONH)
N
ꢀ(4ꢀmethylphenyl)glycyl]amino}ꢀ4ꢀoxoꢀ
1.37 mmol) and sulfanilamide (0.34 g, 2 mmol) in
presence of fused sodium acetate (0.3 g, 3.4 mmol)
was refluxed in ethanol (10 mL) for 4 h. The solid
product was collected, recrystallized from ethanol as
white crystals in 72% yield, m.p. 205–207°C. IR:
3480, 3400, 3380 (NH, NH2), 3030 (CH aromatic),
2900 (CH aliphatic), 1740 (C=O chromene), 1700
4H
c
]chromeneꢀ2ꢀcarboxylate (XVIb)
.
(
p
(
d
δ
J
1
o
J
,
,
(C=O unsaturated ester), 1680 (CONH). H NMR
(
DMSOꢀ
3.80 (2H, s, CH2), 4.00–4.20 (2H,
CH2) 6.20 (1H, s, NHph) 7.50 (2H, s, NH2), 6.70–
7.70 (8H,m, ArH), 10.10 (1H, s, NHCO). Mass;
499.92 [M+– 1]. Found: C, 52.75; H, 3.77; N,
8.42; S, 12.70%. Calculated: C22H19N3O7S2 (501.54):
C, 52.69; H, 3.82; N, 8.38; S, 12.79%.
Ethyl 4ꢀoxoꢀ3ꢀ[( ꢀ{4ꢀ[(pyrimidinꢀ2ꢀylamino)sulfoꢀ
piperidine as greenish yellow crystals in 62% yield, nyl]phenyl}glycyl)amino]ꢀ4 ꢀthieno[3,2ꢀ ]chromeneꢀ2ꢀ
m.p. 283–285°C. IR: 3350 (NH), 3040 (CH aroꢀ carboxylate (XVIg) A mixture of ethyl 3ꢀ[(chloroꢀ
matic), 2920, 2850 (CH aliphatic), 1715 (C=O acetyl)amino]ꢀ4ꢀoxoꢀ ꢀthieno[3,2ꢀ ]chromeneꢀ2
chromene), 1690 (C=O unsaturated ester), 1630 (CO carboxylate (XV) (0.5 g, 1.37 mmol) and sulfadiazine
d
6):
δ
1.25–1.40 (3H,
J
= 7.5 Hz, t, CH3),
.
J
= 6.0 Hz, q,
Found: C, 63.36; H, 4.66; N, 6.38; S, 7.42%. Calcuꢀ
lated: C23H20N2O5S (436.49): C, 63.29; H, 4.62; N,
6.42; S, 7.35%.
,
,
m/z
Ethyl 4ꢀoxoꢀ3ꢀ[(piperidinꢀ1ꢀylacetyl)amino]ꢀ4
thieno[3,2ꢀ ]chromeneꢀ2ꢀcarboxylate (XVIc)
Obtained as the above procedure by the reaction with
Hꢀ
.
c
N
H
c
.
4H
c
ꢀ
1
amide). H NMR (CDCl3):
7.5 Hz, t, CH3), 1.60 (6H, s, 3CH2), 2.30–2.40 (4H, m, (0.3 mL) was refluxed in ethanol (10 mL) for 4 h. The
2CH2), 3.30 (2H, s, CH2) 4.20 (2H, = 6.0 Hz, q, product solid was collected, recrystallized from ethaꢀ
CH2), 7.20–7.80 (4H, m, ArH), 8.00 (1H, s, NH) nol as white crystals in 80% yield, m.p. 222–224°C
Found: C, 60.91; H, 5.28; N, 6.68; S, 7.80%. Calcuꢀ IR: 3400, 3380, 3290 (3NH), 3030 (CH aromatic),
δ
1.35–1.50 (3H,
J
=
(0.4 g, 1.6 mmol) in presence of triethyl amine
,
J
.
.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 5
2013

562
KAMAL ELꢀDEAN et al.
2900, 2850 (CH aliphatic), 1735 (C=O chromene), and hydrazine hydrate (0.6 mL, 0.012 mol) was fused
1700 (C=O unsaturated ester), 1690 (CONH). for 5 min and absolute ethanol (5 mL) was added. The
1H NMR (DMSOꢀ
6): 1.20–1.35 (3H, = 7.5 Hz, reaction mixture was refluxed for 2 h. The precipitated
t, CH3), 4.20–4.45 (2H, = 6.5 Hz, q, CH2) 3.40 (2H, solid which formed on hot during reflux was filtered
s, CH2)
ArH + CH diazine), 8.50 (2H, d, 2CH diazine
11.20 (2H, 2s, NHCO + NHSO2). Mass:
+], 577.1 [
12.12; S, 11.00%. Calculated: C26H21N5O7S2 (579.61):
C, 53.88; H, 3.65; N, 12.08; S, 11.06%.
Ethyl 4ꢀoxoꢀ3ꢀ(5ꢀoxoꢀ3ꢀarylimidazolidinꢀ1ꢀyl)ꢀ4
thieno[3,2ꢀ ]chromeneꢀ2ꢀcarboxylates. General proceꢀ
dure (XVIIa, b) To a solution of compounds (XVIa, b
d
δ
J
J
,
,
6.00 (1H, s, NHph), 7.20–7.60 (9H, m, off, dried and recrystallized from ethanol as white preꢀ
)
, 10.50, cipitate in 71% yield, m.p. >360°C. IR: 3480, 3350,
m/z
579.00 3200 (NH, NH2), 1710 (C=O chromene), 1675 (C=O
1
[M
M
+ – 2]. Found: C, 53.91; H, 3.62; N, carbohydrazide) 1630 (CO pyrimidine). H NMR
(
DMSOꢀd6):
δ
3.90 (2H, s, CH2), 7.00 (2H, s, NH2)
,
7.30–7.70 (4H, m, ArH), 8.60 (1H, s, CONH)
,
11.20
(1H, s, NH pyrimidine). Found: C, 48.26; H, 2.73; N,
15.00; S, 17.20%. Calculated: C15H10N4O4S2 (374.40):
C, 48.12; H, 2.69; N, 14.96; S, 17.13%.
H
ꢀ
c
.
)
(0.5 g, 1.2 mmol) in ethanol (20 mL) and formaldeꢀ
hyde (2 mL) was refluxed for 4 h. The solid obtained
on hot, filtered off, dried and recrystallized from ethaꢀ
nol.
8ꢀ{[2ꢀ(3,5ꢀDimethylꢀ1
hyl]thio}ꢀ6 ꢀchromeno[3',4':4,5]thieno[3,2ꢀ
dineꢀ6,10(9 )ꢀdione (XX) A mixture of hydrazide
XIX) (0.5 g, 1.34 mmol) and acetyl acetone (0.2 mL,
H
ꢀpyrazolꢀ1ꢀyl)ꢀ2ꢀoxoetꢀ
H
H
d]pyrimiꢀ
.
(
2 mmol) was refluxed in ethanol for 2 h. The solid
product which formed on hot, collected and recrystalꢀ
lized from ethanol as orange crystals in 55% yield,
m.p. 340–342°C. IR: 3250 (NH pyrimidine), 3080
(CH aromatic), 2980 (CH aliphatic), 1720 (CO
Ethyl 4ꢀoxoꢀ3ꢀ(5ꢀoxoꢀ3ꢀphenylimidazolidinꢀ1ꢀyl)ꢀ
4Hꢀthieno[3,2ꢀc]chromeneꢀ2ꢀcarboxylate (XVIIa).
Obtained by the above procedure from compound
XVIa) as white crystals in 50% yield, m.p. 236–
238°C. IR: 3050 (CH aromatic), 2950 (CH aliphatic),
1720 (C=O chromene), 1690 (C=O unsaturated ester),
1660 (CO imidazole). Found: C, 63.47; H, 4.25; N,
6.48; S, 7.37%. Calculated: C23H18N2O5S (434.37): C,
63.58; H, 4.18; N, 6.45; S, 7.38%.
(
chromene), 1690 (CH2C=O). 1H NMR (CF3CO2D):
δ
2.70–2.90 (6H, 2s, 2CH3 pyrazole), 4.20 (2H, s, CH2),
7.50–8.20 (4H, m, ArH). Found: C, 54.79; H, 3.21;
N, 12.77; S, 14.63%. Calculated: C20H14N4O4S2
(438.49): C, 54.78; H, 3.22; N, 12.78; S, 14.62%.
Ethyl 3ꢀ[3ꢀ(4ꢀmethylphenyl)ꢀ5ꢀoxoimidazolidinꢀ1ꢀ
2ꢀ[(6,10ꢀDioxoꢀ9,10ꢀdihydroꢀ6
4,5]thieno[3,2ꢀ ]pyrimidinꢀ8ꢀyl)thio]ꢀ
methylene]acetohydrazide (XXI).
H
ꢀchromeno[3',4':
'ꢀ[(1 )ꢀphenylꢀ
mixture of
yl]ꢀ4ꢀoxoꢀ4
H
ꢀthieno[3,2ꢀ
c]chromeneꢀ2ꢀcarboxylate
d
N
A
E
(XVIIb)
.
Obtained by the above procedure from comꢀ
pound (XVIb) as greenish white crystals in 75%, m.p.
200–202°C. IR: 2900–2850 (CH aliphatic), 1725
(C=O chromene), 1700 (C=O unsaturated ester), 1680
hydrazide (XIX) (0.5 g, 1.34 mmol), benzaldehyde
(1 mL, 9.4 mmol) and piperidine (0.5 mL) was heated
under neat conditions for 5 min then the mixture was
refluxed in ethanol (15 mL) for additional 3 h. A pale
yellow precipitate which obtained upon cooling was
recrystallized from ethanol in 70% yield,
m.p. >340°C. IR: 3380, 3100 (2NH), 3050 (CH aroꢀ
1
(CO imidazole). H NMR (CF3CO2D):
δ 1.20–1.35
(3H,
oꢀtolyl
2H,
zole , 7.20–8.00 (8H, m, ArH). Found: C, 64.32; H,
4.52; N, 6.18; S, 7.27%. Calculated: C24H20N2O5S
(448.50): C, 64.27; H, 4.49; N, 6.25; S, 7.15%.
Ethyl[(6,10ꢀdioxoꢀ9,10ꢀdihydroꢀ6 ꢀchromeno[3',4':
4,5]thieno[3,2ꢀ ]pyrimidinꢀ8ꢀyl) thio] acetate (XVIII)
J
= 9.0 Hz, t, CH3 ester), 2.70 (3H, s, CH3
4.10 (2H, s, CH2CO imidazole), 4.30–4.50
J = 8.0 Hz, q, CH2), 5.1 (2H, s, CH2N imidaꢀ
),
(
)
matic), 1725 (C=O chromene), 1650, 1630 (2CONH),
1
1600 (C=N). H NMR (CF3CO2D):
δ
4.10 (2H, s,
CH2), 7.40–7.90 (9H, m, ArH)
,
8.20 (1H, s, CHph).
H
Found: C, 57.20; H, 3.10; N, 12.00; S, 13.95%. Calꢀ
culated: C22H14N4O4S2 (462.51): C, 57.13; H, 3.05; N,
12.11; S, 13.87%.
d
.
A mixture of chloro acetamide derivative (XV) (0.5 g,
1.37 mmol) and slightly excess of potassium thiocynꢀ
ate (0.15 g, 1.55 mmol) in ethanol (5 mL) was refluxed
for 2 h. The solid product was collected and recrystalꢀ
lized from ethanolꢀdioxane mixture (3 : 1) as white
crystals in 66% yield, m.p. 238–240°C. IR: 3300
(NH), 3030 (CH aromatic), 2980–2850 (CH aliꢀ
phatic), 1720 (C=O chromene), 1700 (unsaturated
3ꢀAminochromeno[4,3ꢀc]pyrazolꢀ4(1H)ꢀone (XXII).
Method A. A mixture of 4ꢀchlorocoumarinꢀ3ꢀcarbonꢀ
itrile (IV) (1.5 g, 7.4 mmol) and hydrazine 99%
(0.71 mL) was refluxed in ethanol (20 mL) for 3 h. The
solid precipitate which obtained after cooling filtered
off, dried and recystallized from ethanol as brown
crystals in 80% yield, m.p. >300°C.
ester), 1645 (CONH) cm–1. 1H NMR (DMSOꢀ
1.10–1.30 (3H, = 7.5 Hz, t, CH3), 4.10–4.40 (2H,
= 6.25 Hz, q, CH2) 3.50 (2H, s, CH2), 7.30–8.00
4H, m, ArH), 10.20 (1H, s, NH). Mass: 389.5
+ + 1], 388.62 [ +], 387.62 [ +– 1]. Found: C,
d6): δ
J
Method B. 4ꢀChlorocoumarinꢀ3ꢀcarbonitrile (IV
)
J
,
(1.5 g, 7.4 mmol) and hydrazine hydrate (0.71 mL)
were heated under neat conditions for 1 h. then a few
amount of ethanol was added and reflux was continꢀ
ued for 3 h. The solid precipitate which formed on hot
during reflux was collected and recystallized from ethꢀ
anol in 52% yield, m.p. >300°C. IR: 3400, 3300, 3200
(
m/z
[
M
M
M
52.61; H, 3.18; N, 7.32; S, 16.48%. Calculated:
C17H12N2O5S2 (388.42) C, 52.57; H, 3.11; N, 7.21; S,
16.51%.
2ꢀ[(6,10ꢀDioxoꢀ9,10ꢀdihydroꢀ6
4,5]thieno[3,2ꢀ
]pyrimidinꢀ8ꢀyl)thio] acetohydrazide phatic) 17250 (C=O chromene). 1H NMR (DMSOꢀ
(XIX) A mixture of ester (XVIII) (0.45 g, 1.16 mmol) 6.40 (s, 2H, NH2), 7.20–7.80 (m, 4H, ArH), 8.00
H
ꢀchromeno[3',4': (NH, NH2), 3050 (CH aromatic) 2900, 2850 (CH aliꢀ
d
d6):
.
δ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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2013

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
563
(d, 1H, NH). Found: C, 59.64; H, 3.56; N, 20.93%.
Calculated: C10H7N3O2 (201.19): C, 59.70; H, 3.51;
N, 20.89%.
10ꢀPhenylꢀ6
]pyrimidineꢀ6,8(7
3ꢀaminochromeno[4,3ꢀ
H
ꢀchromeno[4',3':3,4]pyrazolo[1,5ꢀ
)ꢀdione (XXVII) To a solution of
]pyrazolꢀ4(1 ꢀone (XXII
a
H
.
c
H)
)
(0.25 g, 1.25 mmol) in ethanol (5 mL), ethyl benzoyꢀ
lacetate (0.25 mL, 1.25 mmol) was added drop wise
then the mixture was refluxed for 2 h. The solid prodꢀ
uct which was obtained on hot during reflux was filꢀ
tered off, dried and recystallized from ethanol into yelꢀ
low crystals in 84% yield, m.p. 325–327°C. IR: 3430
(NH), 3050 (CH aromatic), 2900, 2850 (CH aliꢀ
phatic), 1720 (C=O coumarin), 1640 (CONH).
8,10ꢀDimethylꢀ6
]pyrimidinꢀ6ꢀone (XXIII). A mixture of 3ꢀamiꢀ
nochromeno[4,3ꢀ ]pyrazolꢀ4(1 ꢀone (XXII) (0.25 g,
Hꢀchromeno[4',3':3,4]pyrazolo[1,5ꢀ
a
c
H)
1.25 mmol)and acetyl acetone (0.20 mL, 2 mmol) was
refluxed in glacial acetic acid (5 mL) for 1.5 h. An
orange crystal was obtained on hot during reflux. The
solid product which formed during reflux was left to
cool then filtered off, dried and recystallized from ethꢀ
1H NMR (DMSOꢀ
9H, m, ArH), 8.20 (1H, s, CH pyrimidine). Found:
C, 69.38; H, 3.30; N, 12.84%. Calculated:
C19H11N3O3 (329.32): C, 69.30; H, 3.37; N, 12.76%.
Ethyl (2 )ꢀ2ꢀcyanoꢀ3ꢀ[(4ꢀoxoꢀ2,4ꢀdihydroꢀ
chromeno[4,3ꢀ ]pyrazolꢀ3ꢀyl)amino]acrylate (XXVIII)
solution of 3ꢀaminochromeno[4,3ꢀ ]pyrazolꢀ
ꢀone (XXII) (0.5 g, 2.5 mmol) in ethanol
d6): δ 6.70 (1H, s, NH), 7.20–7.80
anol as browen solid in 92% yield, m.p. 293–295°C
IR: 3050 (CH aromatic), 2900, 2850 (CH aliphatic),
1725 (C=O). 1H NMR (CF3CO2D):
3.20–3.50 (6H,
2s, 2CH3), 7.40–7.90 (4H, m, ArH), 8.50 (1H, d, CH
pyrimdine). Mass: 267.05 [
+ + 2], 265 [M+
Found: C, 67.87, H, 4.25; N, 15.88%. Calculated:
C15H11N3O2 (265.27): C, 67.92; H, 4.18; N, 15.84%.
10ꢀAminoꢀ6 ꢀchromeno[4',3':3,4]pyrazolo[1,5ꢀ
]pyrimidineꢀ6,8(7 )ꢀdione (XXIV). 3ꢀAmiꢀ
nochromeno[4,3ꢀ ]pyrazolꢀ4(1 ꢀone (XXII) (0.5 g,
.
(
δ
m/
z
M
].
Z
c
.
A
4(1H)
c
H
(10 mL) and ethyl 2ꢀcyanoꢀ3ꢀethoxyacrylate (0.5 g,
3.0 mmol) was refluxed for 3 h. The solid product
which formed on hot during reflux, filtered off, dried
and recrystallized from ethanol into pale buff crystals
in 70% yield, m.p. 280–282°C. IR: 3350, 3290
(2NH), 3050 (CH aromatic), 2900, 2850 (CH aliꢀ
phatic), 2100 (CN), 1720 (C=O chromene), 1690
a
H
c
H)
2.48 mmol) and ethyl cyanoacetate (0.7 mL) were
refluxed in glacial acetic acid (10 mL) for 3 h. The yelꢀ
low crystal was formed on hot recrystallized from
dioxane in 78% yield, m.p. 180°C. IR: 3450, 3300,
3200 (NH + NH2), 2930 (CH aliphatic), 1720 (C=O
(C=O unsaturated ester). 1H NMR (DMSOꢀ
d
6):
= 9.0 Hz, t, CH3), 4.30–4.60 (2H,
= 7.5 Hz, q, CH2), 7.30–8.20 (5H, m, ArH +
CH=C), 10.70 (1H, s, 1NH pyrazole) 11.20 (1H, s,
1
chromene), 1650 (CONH). H NMR (DMSOꢀ
d
6):
δ
1.30–1.55 (3H, J
δ
6.30
4H, m, ArH), 8.40 (1H, s, CH pyrimidine). Mass:
269 [ . Found: C, 58.19; H,
+ + 1], 268.12 [M+
3.00; N, 20.85%. Calculated: C13H8N4O3 (268.23): C,
58.21; H, 3.01; N, 20.89%.
ꢀChromeno[4',3':3,4]pyrazolo[1,5ꢀ
6,8,10(7 ,9 )ꢀtrione (XXV) The mixture of 3–amiꢀ
nochromeno[4,3ꢀ ]pyrazolꢀ4(1 )ꢀone (XXII) (0.50 g,
(2H, s, NH2), 6.90 (1H, s, NH), 7.50–8.10
J
(
m
,
/
z
M
]
NHCH). Found: C, 59.32; H, 3.77; N, 17.34%. Calꢀ
culated: C16H12N4O4 (324.30): C, 59.26; H, 3.73; N,
17.28%.
6H
a]pyrimidineꢀ
Ethylꢀ10ꢀaminoꢀ6ꢀoxoꢀ6
Hꢀchromeno[4',3':3,4]pyꢀ
H
H
.
razolo[1,5ꢀ ]pyrimidineꢀ9ꢀcarboxylate (XXIX) Ethyl
a
c
H
ester (XXVIII) (0.25 g, 0.77 mmol) was refluxed in
acetic acid (10 mL) for 4 h. The solid precipitate which
formed on hot during reflux was collected, dried and
recrystallized form ethanol as white crystals in 80%
yield, m.p. 320–322°C. IR: 3400, 3300 (NH2), 3050
(CH aromatic), 2920, 2850 (CH aliphatic), 1720
(C=O chromene), 1680 (C=O unsaturated ester).
2.5 mmol) and diethyl malonate (0.40 mL, 2.5 mmol)
was refluxed in glacial acetic acid (10 mL) for 3 h. The
solid product which obtained after cooling was filtered
off, dried and recrystallized from dioxane as yellow
crystals in 70% yield, m.p. 315–317°C. IR: 3200
(NH), 3030 (CH aromatic), 2900, 2850 (CH aliꢀ
phatic), 1720 (C=O chromene), 1700, 1660 (2C=O).
1H NMR (CF3CO2D):
t, CH3), 4.30–4.55 (2H,
δ
1.35–1.50 (3H,
J = 7.0 Hz,
1H NMR (DMSOꢀ
d6): δ 3.10 (2H, s, CH2), 6.80 (1H,
J
=6.0 Hz, q, CH2), 7.40–
s, NH), 7.10–8.30 (4H, m, ArH). Found: C, 58.12; H,
2.57; N, 15.67%. Calculated: C13H7N3O4 (269.22) C,
58.00; H, 2.62; N, 15.61%.
8.40 (4H, m, ArH), 8.60 (CH pyrimidine). Found: C,
59.28; H, 3.78; N, 17.34%. Calculated: C16H12N4O4
(324.30): C, 59.26; H, 3.73; N, 17.28%.
8ꢀMethylꢀ6
]pyrimidineꢀ6,10(7
nochromeno[4,3ꢀ ]pyrazolꢀ4(1
2.50 mmol) and ethyl acetoacetate (0.30 mL, A solution of sodium nitrite (0.5 g in 5 mL) was added
2.5 mmol) was refluxed in glacial acetic acid for 3 h. to asolution of 3ꢀaminochromeno[4,3ꢀ ]pyrazolꢀ
ꢀone (XXII) (0.5 g, 2.50 mmol) in concentrated
H
ꢀchromeno[4',3':3,4]pyrazolo[1,5ꢀ
)ꢀdione (XXVI). 3ꢀAmiꢀ
ꢀone (XXII) (0.5 g, razolo[5,1ꢀ
a
H
Ethylꢀ10ꢀaminoꢀ6ꢀoxoꢀ6
Hꢀchromeno[4',3':3,4]pyꢀ
c
H)
c
][1,2,4]triazineꢀ9ꢀcarboxylate (XXXII).
c
The white crystals which was recrystallized from ethaꢀ 4(1H)
nol into 80% yield, m.p. 326–328°C. IR: 3050 (CH HCl (5 mL) with stirring at 0°C then ethanolic soluꢀ
aromatic), 2980 (CH aliphatic), 1725 (C=O chromene), tion of ethyl cyanoacetate (1 mL, 8.85 mmol) in presꢀ
1
1720, 1680 (2C=O). H NMR (CF3CO2D):
δ 2.80 ence of sodium acetate (3 g, 0.034 mmol) was added
(
3H, s, CH3), 6.60 (1H, s, NH pyrimidine), 7.40–8.10 dropwise to the reaction mixture to afford a solid preꢀ
4H, m, ArH), 8.30 (1H, s, CH pyrimidine . Mass: cipitate which was recrystallized from ethanol as redꢀ
= 267 [M+
. Found: C, 62.90; H, 3.36; N, dish brown crystals in 60% yield, m.p. 260°C. IR:
15.65%. Calculated: C14H9N3O3 (267.25): C, 62.92; 3390, 3230 (NH2), 2950 (CH aromatic), 2900, 2850
H, 3.39; N, 15.72%. (CH aliphatic), 1720 (C=O chromene), 1680 (C = O
(
)
m
/
z
]
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 5
2013

564
KAMAL ELꢀDEAN et al.
unsaturated ester). 1H NMR CF3CO2D):
δ
1.50–1.75
REFERENCES
(3H,
CH2), 7.50–8.00 (4H, m, ArH). Mass:
+], 324.5 [ +– 1]. Found: C, 55.42; H, 3.37; N,
21.63%. Calculated: C15H11N5O4 (325.29): C, 55.39;
H, 3.41; N, 21.53%.
J
= 9.0 Hz, t, CH3), 4.70–4.90 (2H,
J
= 7.5 Hz, q,
m/z 325.38
1. Spath, E., Die natiirlichen Cumarine. Ber., 1937,
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[M
M
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no[4,3ꢀ ]pyrazolꢀ3ꢀyl)hydrazono] butanoate (XXXIII)
A solution of sodium nitrite (0.5 g, in 5 mL,
Z)ꢀ3ꢀoxoꢀ2ꢀ[(4ꢀoxoꢀ2,4ꢀdihydrochromeꢀ
c
.
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a
H
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2.5 mmol) in concentrated HCl (5 mL) with stirring at
0°C then ethanolic solution of ethyl acetoacetate
(1 mL, 8.0 mmol) in presence of sodium acetate (3 g,
0.034 mmol) was added dropwise to the reaction mixꢀ
ture to afford a solid precipitate which was recrystalꢀ
lized from ethanol as brown crystals in 50% yield, m.p.
270–272°C. IR: 3300, 3200 (2NH), 3030 (CH aroꢀ
matic), 2900, 2850 (CH aliphatic), 1720 (C=O couꢀ
marin), 1690 (C=O unsaturated ester), 1680
6. Kidane, A.G., Salacinski, H., Tiwari, A., Bruckdorꢀ
fer, K.R., and Seifalian, A.M., Biomacromolecules
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(COCH3), 1610 (C=N). 1H NMR (DMSOꢀ
1.10–1.30 (3H, = 7.5 Hz, t, CH3), 3.80 (3H, s,
COCH3), 4.20–4.50 (2H, = 6.0 Hz, q, CH2), 6.7
d6):
δ
J
9. Delaney, B., Phillips, K., Buswell, D., Mowry, H.B.,
and Nickels, D., Food Chem. Toxicol., 2001, vol. 39,
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J
(1H, s, NH), 7.20–7.80 (4H, s, ArH), 11.20 (1H, s,
NH). Found: C, 56.18; H, 4.20; N, 16.45%. Calcuꢀ
lated C16H14N4O5 (342.31): C, 56.14; H, 4.12; N,
16.37%.
10. Fylaktakidou, K.C., Hadjipavlou, L.D., Litinas, K.E.,
and Nicolaides, D.N., Curr. Pharm. Des., 2004, vol. 10,
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Jean, F.P., Jean, D.B., Mouad, A., Veronique, M., Barꢀ
bara, S., and Jack, M.R., J. Med. Chem., 2007, vol. 50,
pp. 6189–6200.
Testing of Biological Activity
The fungal species were previously isolated from
cases of human dermatophytosis (Moubasher et al.,
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Perti dishes containing sabouraud’s Dextrose agar
(SDA) supplemented with 0.05% chloramphenicol to
suppress bacterial contamination (AlꢀDoory, 1980)
[19] from these cultures, agar discs (10 mm diam.)
containing spores and hyphae were transferred aseptiꢀ
cally to screwꢀtopped vials containing 20 mL sterile
distilled water. After thorough shaking, 1ꢀmL samples
of the spore suspension were pipetted into sterile perti
dishes, followed by the addition of 15 mL liquefied
SDA medium which was then leftto solidify.
12. Brady, H., Desai, S., GayoꢀFung, L.M., Khammuꢀ
ngkhune, S., McKie, J.A., O’Leary, E., Pascasio, L.,
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and Stein B., Cancer Res., 2002, vol. 62, pp. 1439–
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and Blagg, B.S.J., J. Am. Chem. Soc., 2006, vol. 8,
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Cancer, 2000, vol. 60, pp. 5059–5066.
15. Steinfuhrer, T., Hantschmann, A., Pietsch, M., and
Weibenfels, M., Liebigs Am. Chem., 1992, pp. 23–28.
The tested compounds and tolnaftate were disꢀ
solved in DMSO to give 2.0% concentration. Antifunꢀ
gal and antibacterial activities were determined
according to the method reported by Bauer et al.
(1966) [20] using 3ꢀmm diameter filter paper discs
16. Gruner, M., Rehwald, M., Eckert, K., and Gewald K.,
Heterocycles, 2000, vol. 53, pp. 2363–2377.
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macol. Commun., 1999, vol. 5, pp. 315–322.
18. Moubasher, A.H., ElꢀNaghy, M.A., Maghazy S.M.,
(Whatmann No. 3) loaded with 10
under investigation(200 L/disc, 2.0%). The discs
μL of the solution
and ElꢀGendyz., The Korean. J., 1993, vol. 21, pp. 77–84.
μ
19. AlꢀDoory, Y., Laboratory Medical Mycology, Philadelꢀ
phia: Lea and Febiger, 1980, vol. 20, Chap. 19,
pp. 219–241.
were placed on the surface of the fungal cultures which
were incubated at 30°C. The diameter of the inhibition
zone around each disc was measured. The same method
was used for determining antibacterial activity.
20. Bauer, A.W., Kibry, W.M.M., Sherris, J.C., and Truck, M.,
Am. J. Clin. Pathol., 1966, vol.45, pp. 493–496.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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2013