Facile one pot microwave induced solvent-free synthesis and antifungal, antitubercular screening of spiro [1,5]-benzothiazepin-2,3′[3′H] indol-2[1′H]-ones

Article abstract of DOI:10.1248/cpb.51.1137

Microwave activation coupled with dry media technique as a green chemistry procedure has been applied to synthesis of a series of some new title compounds. They have been obtained by the reaction of in situ synthesized 1,3-dihydro-3-[2-(phenyl/4-fluorophenyl)-2-oxoethylidene)-indol-2(1H)-one (4a, b) with substituted aminobenzenethiols (5a - d). The key intermediates 4a, b were also prepared in one step by this improved technique by reacting isatin and substituted acetophenones (2a, b). The results obtained under microwave irradiation when compared with that following conventional method demonstrate the versatility of the process. The title compounds 7a - e have also been screened for their antifungal and antitubercular activity, 7a and 7e showing maximum inhibition of growth of Alternaria alternata and Fusarium oxysporium and 7b, c, e revealing significant antitubercular activity.

Full text of DOI:10.1248/cpb.51.1137

October 2003
Chem. Pharm. Bull. 51(10) 1137—1141 (2003)
1137
Facile One Pot Microwave Induced Solvent-Free Synthesis and Antifungal,
Antitubercular Screening of Spiro [1,5]-Benzothiazepin-2,3؅[3؅H]indol-
2
[1؅H]-ones
,
a
a
a
a
b
Anshu DANDIA,* Meha SATI, Kapil ARYA, Rekha SHARMA, and André LOUPY
a
b
Department of Chemistry, University of Rajasthan; Jaipur 302 004, India: and Laboratoire des Réactions Sélectives Sur
Supports, ICMMO, UMR 8615, Building 410, Université Paris-Sud, 91405 Orsay cedex, France.
Received April 14, 2003; accepted July 22, 2003
Microwave activation coupled with dry media technique as a green chemistry procedure has been applied to
synthesis of a series of some new title compounds. They have been obtained by the reaction of in situ synthesized
1
,3-dihydro-3-[2-(phenyl/4-fluorophenyl)-2-oxoethylidene)-indol-2(1H)-one (4a, b) with substituted aminoben-
zenethiols (5a—d). The key intermediates 4a, b were also prepared in one step by this improved technique by re-
acting isatin and substituted acetophenones (2a, b). The results obtained under microwave irradiation when com-
pared with that following conventional method demonstrate the versatility of the process. The title compounds
7
a—e have also been screened for their antifungal and antitubercular activity, 7a and 7e showing maximum inhi-
bition of growth of Alternaria alternata and Fusarium oxysporium and 7b, c, e revealing significant antitubercular
activity.
Key words spiro[benzothiazepin-indol]-2-one; microwave induced synthesis; dry media technique; biological activity; 3-aroyl-
methylene-2H-indol-2-one; o-aminobenzenethiol
Studies on chemistry and pharmacology of 1,5-benzoth- nipulative advantages over heterogeneous reactions and in
iazepines have provided the famous cardiovascular drugs continuation to our earlier interest on the synthesis of various
3
1—38)
Diltiazem, Clentiazem, etc. to the mankind and those in biodynamic spiro-3-indole derivatives
under MW irra-
which the fused benzene ring is substituted at various posi- diation. So, we report here in a facile and enviro-economic
1
)
tions have been found to be more potent. The research on synthesis of the title compounds 7a—e incorporating two bi-
the chemistry of indoles has continued unabated due to their ologically important heterocycles (1,5-benzothiazepine and
2
—4)
wide spread occurrence in nature and biological activities
indole) with the assumption that the combination of these
and the compounds in which the bio-active indole nucleus is moieties may enhance the biological profile of the compound
spiro fused with another heterocycle at the C-3 position many fold versus its parent nuclei.
5
—7)
shows immense pharmaceutical applications.
Further,
spiro-3-indole derivatives, incorporating five and six mem- Results and Discussion
8
—12)
bered heterocycles have been extensively reviewed
but
The usual thermal procedure for the synthesis of 4a, b re-
3
9)
few reports are available regarding those incorporating a quires a two steps procedure which involves reaction of
seven membered thiazepine moiety. Also, 3-aroyl-2H-indol- isatin (1) with substituted acetophenones (2a, b) in refluxing
2
-ones (4a, b) have been found as the essential synthetic ethanol and Et NH as basic catalyst (3 or 4 drops) to afford
2
1
3—15)
building block
for the synthesis of a wide variety of 3- 1,3-dihydro-3-hydroxy-3-[2-phenyl/4-fluorophenyl-2-oxo-
spiro indolines and condensed indole derivatives. The inves- ethylidene]-indol-2(1H)-ones (3a, b) followed by dehydration
tigation of their reaction with substituted aminobenzenethiols in the presence of a mixture of refluxing glacial AcOH and
to form the title products was found interesting in view of the concentrated HCl afforded 1,3-dihydro-3-[2-(phenyl/4-fluo-
fact that different reaction sites are available in the key inter- rophenyl)-2-oxoethylidene]-indol-2(1H)-one (4a, b).
mediates which may lead to a mixture of products as ob-
However, when the same reaction was studied under MW
served earlier in reactions with several other nitrogen con- irradiation using basic alumina as the inorganic solid sup-
1
6—20)
taining nucleophiles.
port, the compounds 4a, b were obtained in quantitative
The use of microwave (MW) for assisting different organic yields with reasonable purity in 5—6 min without formation
reactions has become very popular in the last few years and of the expected products 3a, b. The usage of basic alumina as
recently the use of supported reagents coupled with MW ir- the mineral support therefore eliminates the necessity of an
2
1—23)
radiation has gained special attention
friendliness and safety. Many review articles
due to its eco- external base for the synthesis of required intermediate 4
2
4—30)
have been which was formed in reasonable purity (TLC) hence used as
published in this field. Due to timeliness, ease of workability, such for further reaction with 5-substituted-2-aminoben-
dramatic rate enhancement and increased selectivity, mi- zenethiols 5a—d to afford the title products 7a—e in a one
crowave technology provides a promising alternative to envi- step procedure whereas a tedious three steps procedure was
ronmentally unacceptable conventional procedures that may required for the same reaction under classical conditions
be time consuming or using toxic, expensive, problematic (Chart 1).
versus pollution and often flammable solvents in large
amounts.
The MW assisted reactions were tried in various mediums
such as basic alumina or montmorillonite KSF as solid sup-
Hence, we were encouraged by the vast potential of rapid ports, ethanolϩconc. HCl, tolueneϩTFA, ethylene glycolϩ
and efficient solvent-less MW induced method that have ma- conc. HCl, ethylene glycolϩpiperidine to check the most ef-
∗
To whom correspondence should be addressed. e-mail: dranshudandia@eth.net
© 2003 Pharmaceutical Society of Japan

1
138
Vol. 51, No. 10
Chart 1
fective condition for the above synthesis. For sake of com- Table 1. Comparative Results Obtained for the Synthesis of 4a, b by Re-
acting 1 and 2a, b
parison, the reaction was also carried out conventionally in
neutral, basic and acidic medium. Positive results were only
b)
Yield
(%)
obtained in acidic medium with lower yields due to the for-
mation of side products and hence required further purifica-
tion and crystallization, while, the reaction in basic medium
gave an intractable mixture which could not be separated into
identifiable pure compounds and reaction did not occur in
neutral medium even on prolonged reflux. From the results of
Table 1, it can be concluded that basic alumina used as the
dry support is the simplest and the most effective catalyst for
the synthesis of 7a and consequently we extended same con-
ditions to synthesize a new series of spiro-fused 1,5-benzoth-
iazepines 7b—e (Table 2).
a) Reaction
Temperature
°C)
Compd.
Method
time
(
(
min)
MW
D
4
a
D (EtOHϩEt NH)
MW (basic alumina)
Reflux
130
130
Reflux
128
128
300
4
300
300
6
—
96
—
—
98
—
72
0
Traces
67
2
c)
d)
D (basic alumina)
4b
D (EtOHϩEt NH)
2
c)
MW (basic alumina)
0
d)
D (basic alumina)
300
17
a) Final temperature is measured at the end of microwave irradiation by introducing
a glass thermometer in the reaction mixture in the beaker. b) Yield of the isolated
products. c) Yield under identical thermal conditions of time and temperature as
under microwaves. d) Yield under identical thermal conditions of temperature, after
Finally, in order to check the possible intervention of spe-
cific (non-thermal) MW effects, the results obtained under extended time.
MW were compared to conventional heating. The reaction, in
the case of compound 7a, has been carried out using pre- tion state, which is more polar due to the negative charge de-
heated oil bath, under the same conditions as under MW localization. The more important stabilization of the transi-
(
time, temperature, vessel) (Table 3).
In all cases it has been found that reactions proceed with electric field is therefore responsible for an enhancement of
considerable lower yields under similar thermal conditions reactivity by a decrease of the activation energy (Chart 2).
tion state by dipole–dipole electrostatic interactions with the
demonstrating that the effect of MW is evidently not purely
This step is followed by intramolecular nucleophilic addi-
4
0,41)
thermal.
These specific non-thermal effects remain no- tion to the carbonyl group involving the formation of a dipo-
ticeable even by extended reaction times up to 6 h, are con- lar transition state, which is stabilized by microwaves (Chart
4
2)
sistent with the consideration of mechanisms and with the 3). Hence, the formation of (7) is substantially accelerated by
assumption that MW effects are increased when the polarity MW under solvent-free conditions.
of a system is enhanced. The rate-determining step consists
in the Michael addition of thiophenol moiety on carbon– sorptions in the region 3405—3138 (N–H), 1695—1680
IR spectra of the final products displayed characteristic ab-
Ϫ1
1
carbon double bond of a,b-unsaturated carbonyl compound. (–NHCO) and 1180—1159 cm (C–N). The H-NMR spec-
One can expect important specific MW effects due to the en- tra showed a singlet at 6.79—6.91 (ϭC–H) and two broad
hancement of polarity of the system during the reaction signals in the region 8.08—8.4 ppm (NH thiazepine, NH in-
progress which is provided by ionic dissociation of the ion dole, exchangeable with deuterium) and at 6.54—7.85 (m,
pairs from the ground state of the reaction towards the transi- aromatic protons). Disappearance of exocyclic CϭC at 1620,

October 2003
1139
Table 2. Analytical and Physical Data of 7a—e
Nitrogen (%)
a)
a)
mp
Time (min)
Yield (%)
Molecular
formula
Compd.
R
X
b)
c)
b)
c)
(
°C)
D /MW
D /MW
Found (Calcd.)
7
a
F
H
H
F
OC H
CH3
OCH3
OCH3
Cl
174—176
145—146
160—162
150—152
155—157
360/15
360/11
420/18
300/14
420/26
47/72
65/66
58/68
48/68
65/73
C H FN O S
6.9 (7.1)
7.4 (7.6)
7.4 (7.2)
7.0 (6.8)
7.5 (7.3)
2
5
24 19
2
2
7
b
C H N OS
23 18 2
7
c
C H N O S
23 18 2 2
7
d
C H FN O S
23 17 2 2
7
e
H
C H ClN OS
22 15 2
a) Time and yield for the compounds isolated from. b) Conventional method, using EtOHϩdry HCl gas. c) in italics, microwave-assisted method using basic alumina as
solid support.
Table 3. Comparative Results Obtained for the Synthesis of 7a by React-
ing 4b and 5a
b)
Reaction
time
Yield (%)
a)
Temperature
Conditions
(
°C)
(
min)
MW
D
c)
d)
d)
EtOHϩHCl
78
17
17
12
15
18
30
58
48
55
72
67
70
Nil (47)
Chart 2
c)
Tolueneϩglacial AcOH
Ethylene glycolϩpiperidine
Basic alumina
108
117
158
110
Nil (19)
c)
30
c)
d)
18 (34)
c)
d)
Montmorillonite KSF
Nil (21)
1
38
—
a) Final temperature is measured at the end of microwave irradiation by introducing
a glass thermometer in the reaction mixture in the beaker. b) Yield of the isolated
products. c) Yield under identical thermal conditions of time and temperature as
under microwaves. d) Yields obtained after extension of reaction time up to 360 min
at similar temperature (under MWs).
Chart 3
1
Table 4. IR and H-NMR Spectral Data of Compounds 7a—e
Ϫ1
1
IR (cm
)
H-NMR d (ppm), J in Hz
Compd.
a)
a)
NH
CϭO
1685
C–N
1159
ϭCH
X
ArH
NH
NH
8.4
8.3
7
a
3400—3145
6.79 (s, 1H)
1.33 (t, Jϭ7, 3H)
.96 (q, Jϭ7, 2H)
2.25 (s, 3H)
3.83 (s, 3H)
3.77 (s, 3H)
—
6.73—7.65 (m, 11H)
8.11
3
7
b
3395—3138
3405—3155
3390—3140
3400—3150
1690
1680
1685
1695
1165
1182
1180
1160
6.80 (s, 1H)
6.83 (s, 1H)
6.91 (s, 1H)
6.86 (s, 1H)
6.9—7.85 (m, 12H)
6.54—7.70 (m, 12H)
6.85—7.74 (m, 11H)
6.75—7.52 (m, 12H)
8.08
8.09
8.2
7
c
8.36
8.33
8.38
7
d
7
e
8.19
a) Exchangeable with deuterium.
Ϫ1
CϭO absorption at 1670 cm and retention of NHCO peak Table 5. In Vitro Evaluation of Antitubercular Activity against Mycobac-
Ϫ1
terium Tuberculum
at 1680—1695 cm indicated the participation of a,b-unsat-
urated carbonyl system of side chain of 4 resulting in the for-
mation of spiro heterocycle at position 3 of 2-indolinone.
MIC
mg/ml)
Compd.
X
% Inhibition
(
Further, the absence of primary amino group absorption at
Ϫ1
3
450 and 3350 cm confirmed the formation of 1,5-ben-
7a
OC H
CH3
Ͼ12.5
Ͼ12.5
Ͼ12.5
Ͼ12.5
Ͼ12.5
97 ϩ
99 ϩ
99 ϩ
92 ϩ
100 ϩ
2
5
7
b
zothiazepine ring system ruling out the possibility of 6
7
c
OCH3
OCH3
Cl
(
Table 4).
7
d
1
3
C-NMR spectrum of 7a showed signals at
CDCl ϩ(CD ) SO] 14.1, OCH CH , 56.8, spiro carbon;
1.6, OCH CH ; 94.2, C-3; 138.9, C-4; 155.3, C-8; 165.4,
CϭO; 111.1—149.0, 18 aromatic ring carbon atoms. The
presence of fluorine was confirmed by
d and 7a where the C–F signal was observed at d
CDCl ϩ(CD ) SO] Ϫ119.05 and Ϫ118.73 ppm respec-
d
7
e
[
6
3
3 2
2
3
MIC RMPϭ0.25 mg/ml, 98% inhibition vs. M. tuberculosis. ϩ Inhibition greater
than 90%, % inhibitionϭactivity of each compound at the 12.5 mg/ml level. Final col-
umn lists the minimum inhibitory concentration of a control drug for comparison.
2 3
4
0,41)
F-NMR spectra of MICϭminimum inhibitory concentration in mg/ml.
7
[
Evaluation of Antitubercular Activity The antituber-
3
3 2
tively. In the mass spectra of 7b and 7a, molecular ion peaks cular evaluation of the compounds was carried out by the
were observed at m/z 370 (3.7%) and 418 (2.2%) corre- “Tuberculosis Antimicrobial Acquisition and Coordinating
sponding to the molecular formula C H N OS and facility” (TAACF) in U.S.A. Primary screening of the com-
2
3
18
2
C H FN O S respectively.
pounds have been conducted at 12.5 mg/ml against Mycobac-
24
19
2
2

1
140
Vol. 51, No. 10
Table 6. Effect of Synthesized Compounds 7a—e on the Radial Growth of Different Fungi
Radial growth (in cm) and percent inhibition of
Radial growth (in cm) and percent inhibition of
Alternaria alternata
Fusarium oxysporium
Cmpd.
Check 0 ppm 500 ppm
% Inhibition 1000 ppm % Inhibition Check 0 ppm 500 ppm
% Inhibition 1000 ppm % Inhibition
7
a
5.10
3.30
3.30
5.10
3.30
2.40
1.50
1.30
3.10
1.30
52.94
54.54
60.60
39.21
60.60
1.50
1.00
1.00
0.70
0.80
70.58
69.69
69.69
86.27
75.75
4.50
3.50
3.50
4.50
3.50
1.80
2.50
2.10
2.80
1.30
60.00
28.57
40.00
37.77
62.85
1.50
1.30
1.10
2.00
1.80
48.57
62.85
68.57
55.55
66.66
7
b
7
c
7
d
7
e
Each observation on average of three replications. Percent growthϭ[radial growth in check (cm)Ϫradial growth in treatment (cm)]/[radial growth in check (cm)]ϫ100.
4
6)
terium tuberculum H37 RV, in BACTEC 12 B medium using from ethanol to give red needles of 4b. mpϭ185—187 °C (Lit. 187 °C);
4
3)
yield, 67%.
BACTEC 460 radiometric system. Antitubercular activity
data were compared with standard drug Rifamipin at
0
Microwave Mediated Synthesis: An equimolar mixture of indole 2,3-
dione (1) (10 mmol, 1.47 g) and 4-fluoroacetophenone (2b) (10 mmol,
.25 mg/ml concentration which showed 98% inhibition.
Compounds 7a—e showed 97, 99, 97, 92 and 100% activity
1
.38 g) was adsorbed separately on basic alumina (20% by weight of the re-
actants) via a solution in acetone, mixed thoroughly and irradiated in a do-
respectively (Table 5), which were further screened for level- mestic MW oven (700 W, generating 2450 MHz frequency) at an emitted
power of 640 W for 5—6 min at 128 °C (monitored by T.L.C.). The product
2
screening.
was extracted by eluting with ethanol. Excess solvent was evaporated on
Evaluation of Antifungal Activity The synthesized
water bath to give red crystals of the chalcone. mp 186 °C, yieldϭ98%.
compounds 7a—e were screened for antifungal activity
46)
Likewise 4a was prepared by the same procedure. mp 195 °C (Lit.
against Alternaria alternata and Fusarium oxysporium in 196 °C), yield, 96%.
4
4)
three replications by ‘Food poision technique. Each of the
compound was dissolved in 20% acetone at 1000 and
5
8-Ethoxy-2,5-dihydro-(4-fluorophenyl)-spiro[[1,5]-benzothiazepin-
,3Ј[3ЈH]-indol]-2Ј(1ЈH)-one 7a was also synthesized by two different ways:
i) a conventional method, (ii) a MW assisted method.
Conventional Method: The reactions of 4b and 5a were tried in three dif-
2
(
00 ppm concentrations, which was then added, in required
quantities, to Potato Dextrose Agar (PDA) medium, in three
ferent reaction media, viz. neutral (dry toluene), basic (dry tolueneϩpiperi-
replicates before dispersing into petriplates. Standard checks dine) and acidic (dry ethanol saturated with hydrogen chloride gas). No sig-
were also prepared by inoculating fungi in PDA media for nificant results were obtained in neutral and basic media and spiro com-
pound was obtained exclusively in acidic medium using EtOHϩdry HCl gas
as follows:
A solution of 4b (1 mmol, 267 mg) in absolute ethanol (15 ml) was satu-
comparison. After 7 d of incubation at 25 °C, radial growth
of the colony was measured. The data obtained were statisti-
cally analyzed using completely randomized design and aver-
ages compared using critical difference at 0.05% probability.
These compounds 7a—e are more effective against Al-
ternaria alternata than Fusarium oxysporium. The concen-
trations of the compounds greatly influence their efficiency in
reducing fungus growth (Table 6).
rated with hydrogen chloride gas when the red colored solution turned
brown. To this, a solution of 5-ethoxy-2-aminobenzenethiol (5a) (1 mmol,
1
69 mg) in absolute ethanol (5 ml) was added slowly with continuous stir-
ring when the solution darkened further. It was refluxed for 4—6 h till the
completion of reaction, as monitored by T.L.C. The reaction mixture was
cooled and kept in refrigerator for 12 to 48 h. Solid thus obtained was fil-
tered, washed with saturated NaHCO , dried and crystallized from dry
3
methanol to obtain the title compound 7a. The reaction was also tried in
tolueneϩTFA and the results are summarized in Table 1.
Experimental
Melting points were determined in open glass capillaries and were uncor-
Microwave Assisted Synthesis: (1) Using various solvents. An equimolar
rected. Thin layer chromatography on silica gel ‘G’ coated glass plates using mixture of 4b and 5a was dissolved in the minimum amount of an appropri-
benzene, ethanol and ammonia (7 : 2 : 1) as eluent was used for monitoring ate solvent required to form slurry, for e.g. (a) ethanolϩconc. HCl, (b)
progress of the reactions. IR spectra (KBr) were recorded on a Magna FT tolueneϩTFA, (c) ethylene glycolϩconc. HCl, (d) ethylene glycolϩpiperi-
1
19
13
IR-550 spectrophotometer, H- and F- and C-NMR spectra [CDCl ϩ
dine etc. in an open borosil vessel. It was irradiated inside a MW oven at an
CD ) SO] were taken on a Jeol FX 90Q spectrometer at 89.55, 84.25 and appropriate power output for an adequate time (Table 1) till the reaction was
3
(
3
2
2
2.49 MHz respectively, using TMS as an internal standard for PMR and found to complete as indicated by T. L. C. Reaction mixture was cooled and
19
hexafluorobenzene as external standard for F-NMR and mass spectra were poured over crushed ice in the last two cases (c) and (d). The crystalline
recorded on Jeol D-300 spectrometer at an ionisation potential of 70 e.v. Mi- product separated out immediately on cooling in case of (a) and (b). The
crowave assisted reactions were carried out on a BPL BMO model, operat- crystals thus obtained were filtered, dried and recrystallized from methanol
ing at 700 W, generating 2450 MHz frequency.
to obtain the title compounds 7a (Table 1).
5
-Chloro/methyl/methoxy/ethoxy-2-aminobenzenethiols (5a—d) were
(2) Using various inorganic solid supports in dry media. Equimolar quan-
tities of 4b and 5a were adsorbed separately on montmorillonite KSF or
basic alumina (20% by weight of the reactants) via a solution in ethyl ac-
etate, mixed thoroughly and irradiated for an appropriate time at 640 W until
4
5)
synthesized according to literature reported methods.
1
,3-Dihydro-3-[2-(4-fluorophenyl)-2-oxoethylidene]indol-2(1H)-one (4b)
was prepared by two different ways:
Conventional Synthesis Involving a Two Steps Procedure: 1,3-Dihydro-3- the completion of the reaction (monitored by T. L. C.). The recyclable inor-
hydroxy-3-(4-fluorophenyl-2-oxoethylidene)-indol-2(1H)-ones (3b)
Step 1. An equimolar mixture of indole 2,3-dione (1) (10 mmol, 1.47 g)
and 4-fluoroacetophenone (2b) (10 mmol, 1.38 g) was refluxed on a water
bath for 4—5 h in absolute ethanol (15 ml) containing 3—5 drops of diethyl-
ganic solid support was separated by filtration after eluting the product with
ethanol. The solvent was evaporated to give the crystalline product 7a of
reasonable purity. (Table 3).
Comparison of the results obtained by the conventional and MW methods
amine. On cooling, yellow coloured crystals separated out which were fil- proved basic alumina to be the most effective support. Likewise, following
tered and recrystallized from methanol to give white needles. mpϭ172 °C
the same procedure compounds 7b—e were prepared and their structural
characterization was done on the basis of IR, H-NMR and spectral and ele-
46)
1
(
Lit. 170 °C); yieldϭ74%.
Step 2. The compound 3b (10 mmol, 1.47 g) was refluxed with a mix- mental analysis (Tables 2, 4).
ture of glacial acetic acid (15 ml) and conc. hydrochloric acid (5 ml) on a
water bath for 1 h. The reaction mixture was cooled to room temperature. A
Acknowledgements Financial Assistance from UGC and C.S.I.R., New
red colored compound separated out which was filtered and recrystallized Delhi is gratefully acknowledged. We are also thankful to RSIC, CDRI, Luc-

October 2003
1141
know, for the elemental and spectral analyses and to “Tuberculosis Antimi- 23) Bram G., Loupy A., Villemin D., “Solid Supports and Catalysts in Or-
crobial Acquisition and Coordinating facility” (TAACF) U.S.A. for anti-tu-
bercular screening of the compounds. We are also grateful to Dr. I. J. Gupta,
ganic Synthesis,” ed. by Smith K., Ellis Horwood Ltd., Chichester,
1992, p. 302.
Seed Technology Research Centre, Agricultural Research Station, Durga- 24) “Microwaves in Organic Synthesis,” ed. by Loupy A., Wiley-VCH,
pura (Jaipur), for evaluating the anti-fungal activity of the compounds.
Weinheim (Germany), 2002.
2
5) Jeselnik M., Varma R. S., Polanc S., Kocevar M., Green Chem., 4,
35—38 (2002).
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