Microwave-induced solvent-free synthesis and antifungal screening of novel spiro heterocyclic systems containing 3,5-diphenyl-7h-thiazolo[3,2-a]pyrimidine and indolin-2-one

Article abstract of DOI:10.1080/00397911.2013.769604

A microwave-induced technique has been developed for the synthesis of a series of novel spiro indoline-based heterocycles (7a-g) at atmospheric pressure in an open vessel using an environmentally benign procedure. This rapid method produces pure products

Full text of DOI:10.1080/00397911.2013.769604

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Microwave-Induced Solvent-Free
Synthesis and Antifungal Screening
of Novel Spiro Heterocyclic Systems
Containing 3,5-Diphenyl-7H-
thiazolo[3,2-a]pyrimidine and Indolin-2-
one
Divya Singh a , Shahin Fatma a , Preyas Ankit a , Priya Mishra a ,
Sarita Singh a , Shyam Babu Singh a & Jagdamba Singh a
a Environmentally Benign Synthesis Laboratory, Department of
Chemistry , University of Allahabad , Allahabad , India
Accepted author version posted online: 18 Jun 2013.Published
online: 08 Aug 2013.
To cite this article: Divya Singh , Shahin Fatma , Preyas Ankit , Priya Mishra , Sarita Singh , Shyam
Babu Singh & Jagdamba Singh (2013) Microwave-Induced Solvent-Free Synthesis and Antifungal
Screening of Novel Spiro Heterocyclic Systems Containing 3,5-Diphenyl-7H-thiazolo[3,2-a]pyrimidine
and Indolin-2-one, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:22, 3072-3082, DOI: 10.1080/00397911.2013.769604
To link to this article: http://dx.doi.org/10.1080/00397911.2013.769604
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Synthetic Communications1, 43: 3072–3082, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.769604
MICROWAVE-INDUCED SOLVENT-FREE SYNTHESIS
AND ANTIFUNGAL SCREENING OF NOVEL SPIRO
HETEROCYCLIC SYSTEMS CONTAINING
3,5-DIPHENYL-7H-THIAZOLO[3,2-a]PYRIMIDINE AND
INDOLIN-2-ONE
Divya Singh, Shahin Fatma, Preyas Ankit, Priya Mishra,
Sarita Singh, Shyam Babu Singh, and Jagdamba Singh
Environmentally Benign Synthesis Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
GRAPHICAL ABSTRACT
Abstract A microwave-induced technique has been developed for the synthesis of a series
of novel spiro indoline-based heterocycles (7a–g) at atmospheric pressure in an open ves-
sel using an environmentally benign procedure. This rapid method produces pure products
in good yields within a few minutes in comparison to the conventional procedure developed
for the synthesis of these heterocycles. The synthesized compounds have been screened
in vitro for antifungal activity against two fungal strains (i.e., Aspergillus niger and
Aspergillus flavus). All compounds have shown significant activity against these
pathogens.
[Supplementary materials are available for this article. Go to the publisher’s
online edition of Synthetic Communications1 for the following free supplemental resource:
Full experimental and spectral details.]
Received October 7, 2012.
Address correspondence to Jagdamba Singh, Environmentally Benign Synthesis Laboratory,
Department of Chemistry, University of Allahabad, Allahabad 211002, India. E-mail: dr.jdsau@
gmail.com
3072

NOVEL SPIRO HETEROCYCLIC SYSTEMS
3073
Keywords Michael addition; microwave-assisted solvent-free synthesis; solid support
technique; spiro indoline-based heterocycles
INTRODUCTION
During the past 20 years, an increase of invasive fungal infections has been
observed, which is the major cause of morbidity and mortality in immunosup-
pressed patients. It is in this regard that there is still a critical need for new
antifungal agents to treat life-threatening invasive mycoses.[1] To overcome this
rapid development of drug resistance, new agents should preferably consist of
chemical characteristics that clearly differ from those of existing ones. In drug
designing methodology, an essential component of the search for new leads is
the synthesis of molecules, which are novel yet resemble known biologically
active compounds because of the presence of critical structural features. Certain
small heterocyclic molecules act as highly functionalized scaffolds and are
known pharmacophores of a number of biologically active and medicinally
useful molecules.[2,3]
Electron-rich nitrogen heterocycles play important roles in diverse biological
activities. Studies on chemistry and pharmacology of pyrimidines (electron-rich
nitrogen compounds) are of great importance in fundamental metabolism. They
are found to possess diverse biological properties such as bactericidal, fungicidal,
antiviral, insecticidal, activities and meticidal.[4] The research on the chemistry of
indoles has continued unabated because of their remarkable biological activities
and widespread occurrence in nature.[5–7] The compounds having bioactive indole
nucleus spiro fused with another heterocycle at the C-3 position show many
pharmaceutical applications.[8–10] In particular, spiro-3-indole derivatives incor-
porating five-and six-membered heterocycles have been extensively studied.[11–15]
It is well known that 3-aroyl-2H-indol-2-one (4) has been used as an essential syn-
thetic building block[16–18] for the synthesis of a wide variety of 3-spiro indolines
and condensed indole derivatives. Hence, we found it interesting to investigate
its reaction with substituted 2-amino-4-phenylthiazoles (which are used as
precursors for the synthesis of biologically active molecules) to form the new
spiro heterocyclic system containing 7H-thiazolo [3, 2-a]pyrimidine and benzo
[b]azet-2(1H)-one. Both conventional thermal and microwave-assisted methods
have been developed. The use of microwave (MW) for assisting different organic
reactions has become very popular in the past few years[19,20] and recently the use
of supported reagents coupled with MW irradiation has gained special atten-
tion[21,22] because of its ecofriendly nature and safety in use. Therefore, we report
here a facile, environmentally benign, and economic synthesis of the spiro com-
pounds 7a–g incorporating two biologically important heterocycles (i.e.,
substituted-2-amino-4-phenylthiazoles and indole), with the assumption that
the combination of these moieties may enhance the biological profile of the
compound manyfold versus its parent nuclei. Target compounds contain
spiro-thiazolopyrimidine[23] derivatives which show antiviral, analgesic, and
antimicrobial activities.

3074
D. SINGH ET AL.
RESULTS AND DISCUSSION
The usual thermal procedure for the synthesis of compound 4 requires two
steps[24] involving the reaction of isatin 1 with acetophenone 2 in refluxing ethanol
and Et3N as basic catalyst to afford 1,3-dihydro-3-hydroxy-3-[2-(phenyl)-
2-oxoethylidene]-indol-2(1H)-one, 3 followed by dehydration in the presence of a
mixture of refluxing glꢀAcOH and concentrated HCl, affording 1,3-dihydro-3-
[2-(phenyl)-2-oxoethylidene]-indol-2(1H)-one, 4. The entire process took 300 min
to yield the product. However, when the same reaction was studied under MW
irradiation using basic alumina as the inorganic solid support, the compound 4
was obtained in quantitative yield with reasonable purity in 5–6 min without forma-
tion of the product 3 (Table 1).
The usage of basic alumina as mineral support thus eliminates the necessity of
an external basic catalyst for the synthesis of required intermediate 4, which was
formed in reasonable purity. Therefore, it was used as such for further reaction with
substituted-2-amino 4-phenyl thiazoles 5a–g to afford the spiro compounds 7a–g in a
one step procedure, whereas a tedious three-step procedure was required for the
same reaction under classical conditions (Scheme 1). Apart from basic alumina,
the MW-assisted reactions were also tried in various mediums such as montmorillon-
ite KSF as solid support, ethanol=concentrated HCl, toluene=glacial (gl)ꢀAcOH, eth-
ylene glycol=piperidine, and 1,4-dioxane to check the most effective condition for the
synthesis. For sake of comparison, the reaction was also carried out conventionally
in neutral, basic, and acidic media. In the acidic medium, the yield was poor due to
formation of side products, and hence the desired product required further purifi-
cation and crystallization. The reaction in the basic medium gave an intractable mix-
ture that could not be separated into identifiable pure compounds. We observed that
the optimum product was obtained in the neutral medium. All these results are sum-
marized in Table 2, from which 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.
Finally, to check the possible intervention of specific (nonthermal) MW effects,
the results obtained under MW were compared to that of conventional heating. The
reaction, in the case of compound 7a, has been carried out using a preheated oil
bath, under the same conditions as under MW (time, temperature and vessel)
(Table 2). Consequently we extended the same conditions to synthesize a new series
of spiro-fused target molecules 7b–7g (Table 3).
In all cases, reactions proceed with considerably lower yields under similar
thermal conditions, demonstrating that the effect of MW is evidently not purely ther-
mal.[25,26] These specific nonthermal effects remained noticeable even by extended

NOVEL SPIRO HETEROCYCLIC SYSTEMS
3075
Scheme 1. Conventional and microwave synthesis of intermediate 4 and compounds 7a–7g.
reaction times up to 6 h for conventional method and were consistent with the con-
sideration of mechanisms[27] and with the assumption that MW effects are increased
when the polarity of a system is enhanced. The rate-determining step can be assumed
to be the Michael addition of substituted 2-amino 4-phenyl thiazole moiety on
carbon–carbon double bond of a, b-unsaturated carbonyl compound, which pro-
ceeds through transition state I (TSI) (Scheme 2a). One can expect important specific

3076
D. SINGH ET AL.
Table 1. Comparative results obtained for the synthesis of 4 by reaction of 1 and 2
Yielda (%)
Condition
Temperature (ꢂC)
Reaction time (min)
MW
D
(a) D=EtOHþEt3N
(b) D=gl ꢀ AcOH conc ꢀ HCl
Basic alumina
Reflux
Reflux
130
300
60
—
72
5–6
300
96
—
0b
Tracesc
Basic alumina
130
aYield of the isolated products.
bYield under identical thermal conditions of time and temperature as under micrcowaves.
cYield under thermal condition (at same temperature as in the case of MW), after extended time.
MW effects due to the enhancement in polarity of the system during the reaction
progress, which is provided by dissociation of bond pairs from the ground state of
the reaction to the transition state, which is more polar because of the negative
charge delocalization. This more significant stabilization of the transition state by
dipole–dipole electrostatic interactions with the electric field is therefore responsible
for enhancement of reactivity by a decrease in the activation energy. This step is fol-
lowed by intramolecular nucleophilic addition to the carbonyl group involving the
formation of a dipolar transition state II (TSII) (Scheme 2b), which is also stabilized
by microwaves.
Hence, the formation of 7 is substantially accelerated by MW under
solvent-free conditions. Infrared (IR) spectra of the final products displayed charac-
teristic absorptions in the region 1695–1665 (–NHCO). The 1H NMR spectra
showed a singlet at 4.60–5.71 (¼ C–H) and signals in the regions 7.47–8.11 ppm
=
(NH indole, exchangeable with D2O). Disappearance of exocyclic C C vibrations
at 1620, C O vibrations at 1670 cmꢁ1, and retention of NHCO peak at
=
1695–1665 cmꢁ1 in IR spectra indicated the participation of a, b-unsaturated car-
bonyl system of side chain of 4, which results in the formation of spiro heterocycle
at position 3 of 2-indolinone. Further, the absence of secondary amino group vibra-
tions at 3450 and 3350 cmꢁ1 confirmed the formation of a pyrimidine ring system
and ruled out the possibility of 6 (Table 4). The mass spectrum of 7a had shown a
Table 2. Comparative result obtained for the synthesis of 7a by reacting 4 and 5a
Yielda (%)
Conditions
Temperature (ꢂC)
Reaction time (min)
MW
D
EtOH=HCl
82
104
115
148
112
98
17
18
15
13
20
32
60
52
58
85
70
65
Nilb
Nilb
35b
40c
21c
Toluene=gl ꢀ AcOH
Ethylene glycol=piperidine
Basic alumina
22b
34c
25c
52c
Montmorillonite KSF
1,4-Dioxane
Nilb
Nilb
aYield of the isolated products.
bYield under identical thermal conditions of time and temperature as under microwaves.
cYield obtained after extension of reaction time up to 360 min at similar temperature (under same con-
ditions as MW).

NOVEL SPIRO HETEROCYCLIC SYSTEMS
3077
Table 3. Physical data (melting point and yield) of 7a–g
D
MW
Entry
Compound
Mp (ꢂC) Time (min) Yield (%) Time (min) Yield (%)
7a
172–174
148–150
240
240
52
68
15
11
85
83
7b
7c
7d
7e
7f
152–154
156–158
162–164
153–155
240
300
300
420
65
58
55
48
13
18
19
26
80
82
80
86
7g
158–160
420
52
30
88
Time and yield for the compounds isolated from conventional method (using 1,4-dioxane) and
microwave-assisted method using basic alumina as solid support.
molecular ion peak at m=z 407.1 corresponding to the molecular formula
C25H17N3OS.
To study pharmacokinetics and extent of drug likeliness of synthesized com-
pounds, the extended Lipinski’s rule along-with certain other parameters is used,
as outlined by Young.[28] Table 5 shows comparison of ideal values against those
calculated for compounds 7a–7g. As is clear Table 5, all entries follow Lipinski’s
criteria except compound 7c, which is having one Lipinski’s failure due to a little

3078
D. SINGH ET AL.
Scheme 2. Transition states I and II.
increment in log P value relative to ideal value. This slight increment in log P can be
compensated by optimum values of other descriptors, and hence it is concluded that
all compounds 7a–7g are pharmacokinetically active potential drug candidates.
Further, Table 6 shows HOMO and LUMO energies calculated for 7a–7g and fluco-
nazole. The highest occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) energy analysis revealed that compound 7g is most
electrophilic because of the lowest value of ELUMO and compounds 7b, 7c, and 7e
Table 4. C O vibrations and 1H NMR spectral data (excluding aromatic H) of compounds 7a–g
=
1H NMR (d ppm)
IR (cmꢁ1
CO
)
Compound
¼CH
X
NH
7a
7b
7c
7d
7e
7f
1685
1680
1679
1670
1665
1690
1695
5.71
4.61
4.60
4.61
4.61
5.02
5.04
—
2.40 (s, 3H)
8.09
8.11
8.11
8.11
8.11
7.76
7.47
1.22 (t,3H), 2.81 (q,2H)
4.76 (s, 1H)
3.84 (s, 3H)
—
—
7g
Table 5. Tabulated properties of compounds 7a–g
Molecular Log
weight
TPSA
H bond
donor
H bond
acceptor
Lipinski’s
failures
Number of rotat-
able bonds
2
˚
Entry
P
(A )
7a
7b
407.109
421.124
435.140
423.104
437.119
441.070
452.094
306.104
500.000
4.173 70.000
4.565 70.000
5.029 70.000
3.459 90.230
3.780 79.230
4.117 70.000
3.757 113.140
1.900 81.650
5.000 <140.000
1
1
4
0
0
2
2
4
7c
7d
1
4
1
3
2
5
5
0
2
7e
1
0
3
7f
7g
1
4
0
2
1
7
0
3
Fluconazole
Ideal values
1
7
0
—
5
ꢃ5
ꢃ10
ꢃ5

NOVEL SPIRO HETEROCYCLIC SYSTEMS
3079
Table 6. HOMO and LUMO energies of compounds 7a–g
Entry
EHOMO (eV)
ELUMO (eV)
g ¼ (ELUMO ꢁ EHOMO)=2
7a
7b
ꢁ8.35
ꢁ8.30
ꢁ8.31
ꢁ8.35
ꢁ8.29
ꢁ8.45
ꢁ8.66
ꢁ10.35
ꢁ0.52
ꢁ0.45
ꢁ0.46
ꢁ0.53
ꢁ0.45
ꢁ0.76
ꢁ1.74
ꢁ0.97
3.915
3.925
3.925
3.910
3.920
3.845
3.460
4.690
7c
7d
7e
7f
7g
Fluconazole
are least electrophilic in nature because of the higher values of ELUMO. It is also
noteworthy that compounds 7a, 7b, and 7c possessed the greatest value of g (index
of intrinsic reactivity), indicating their least reactivity.
The synthesized title compounds were then evaluated for the antifungal activity
against two phytopathogenic fungal strains (viz. Aspergillus flavus and Aspergillus
niger) by paper disc technique against two concentrations, 500 mg=mL and
1000 mg=mL. The zone of inhibition after 24 h of incubation at 28 ꢂC ꢄ 2 ꢂC was com-
pared with that of identical concentrations of standard fluconazole. The data of anti-
fungal tests are depicted in Table 7. A close survey of the zone of inhibition (%)
values indicates that all the compounds 7a–g exhibit a varied range (zone of
inhibition ¼ 25–58% at 500 mg=mL and 30–69% at 1000 mg=mL) of antifungal
activity against both the tested fungal strains.
The screening data indicated that among all the derivatives, 7e and 7f showed
excellent and broad spectrum of activity against both fungal species at 500 mg=mL as
well as 1000 mg=mL concentrations, whereas compounds 7d and 7g showed good to
moderate activity at both the concentrations. Low to moderate activity was observed
for compounds 7a, 7b, and 7c against two tested species as shown in Table 7. This is
in accordance with that expected for these compounds from g values.
Table 7. In vitro antifungal activity of newly synthesized title compounds (7a–g)
Zone of inhibition (%)a
Aspergillus niger
Aspergillus flavus
500 mg 1000 mg
No.
Compound
7a
7b
X
500 mg
1000 mg
1
2
3
4
5
6
7
8
H
CH3
C2H5
OH
42
40
35
45
50
58
44
70
50
48
44
56
65
69
58
80
26
25
21
36
44
46
25
58
35
34
30
45
52
54
40
70
7c
7d
7e
OCH3
Cl
7f
7g
NO2
—
Standard
fluconazole
aEach value is the mean of three independent experiments.

3080
D. SINGH ET AL.
Furthermore, some interesting results have been obtained through a
comparative study on the structure activity relationship of all compounds. Com-
pounds having no substituent at ortho, meta, and para positions of the phenyl ring
(2-amino 4-phenyl thiazole) showed a moderate zone of inhibition (7a). Interestingly,
if the methoxy group was introduced at the the para position of phenyl ring, the cor-
responding derivative possessed potent activity with significant inhibitory zone (7e).
Moreover, compounds having electron-withdrawing chloro substituent at the para
position of the phenyl ring exerted excellent activity with maximum zone of inhi-
bition (7f). Introduction of methyl and ethyl group at the phenyl ring of compounds
(7b) and (7c), respectively, have not shown any remarkable change in the antifungal
activity.
EXPERIMENTAL
Synthesis of 1,3-Dihydro-3-[2-(phenyl)-2-oxoethylidene]indol-2(1H)-
one (4)
This compound was prepared using two different methods: (i) conventional
method and (ii) MW-assisted method.
Conventional synthesis involving a two-step procedure.
Step 1. An equimolar mixture of indole 2,3-dione (1) (10 mmol, 1.47 g) and
acetophenone (2) (10 mmol) was refluxed on a water bath for 4–5 h in absolute
ethanol (15 ml) containing 3–5 drops of triethylamine. On cooling, yellow crystals
separated out, which were filtered and recrystallized from methanol to give white
needles of compound 3.
Step 2. Compound 3 (10 mmol) was refluxed with a mixture of glacial acetic
acid (15 ml) and concentrated hydrochloric acid (5 ml) on a water bath for 1 h. The
reaction mixture was cooled to room temperature. A red compound separated out
which was filtered and recrystallized from ethanol to give red needles of compound
4 (mp195 ꢂC (lit.[29] 196 ꢂC); yield, 72%).
Microwave-mediated synthesis. An equimolar mixture of indole 2,3-dione
(1) (10 mmol) and acetophenone (2) (10 mmol,) was adsorbed separately on basic
alumina (20% by weight of the reactants) via a solution in acetone, mixed thor-
oughly, and irradiated in MW (BP-310 laboratory microwave, Microwave Research
and Applications, Inc., USA) for 5–6 min at 128 ꢂC. The product (monitored by
thin-layer chromatography, TLC) was extracted by eluting with ethanol. Excess sol-
vent was evaporated on water bath to give red crystals of the compound 4 (mp
195 ꢂC, yield 96% (lit.[29] 196 ꢂC).
Spiro Heterocyclic System Containing 7H-Thiazolo[3,2a]pyrimidine
and Benzo[b]azet-2(1H)-one (7a)
This synthesis also involved two different methods: (i) conventional method
and (ii) MW-assisted method.

NOVEL SPIRO HETEROCYCLIC SYSTEMS
3081
Conventional method. The reactions of 4 and 5a were tried in different
reaction media: neutral (1,4 dioxane), basic (ethylene glycol=piperidine), and acidic
(dry ethanol saturated with hydrogen chloride gas). Significant results were obtained
in neutral media, and therefore it was used as the preferred medium for all further
reactions. An equimolar mixture of compound (4) (1 mmol) and 2-amino-4-phe-
nylthiazole (5a) (1 mmol) was dissolved in a minimum amount of 1,4-dioxane and
the solution was refluxed for 4–5 h. The reaction mixture was cooled and poured in
water. The yellowish precipitate thus obtained was washed with water and
recrystallized from benzene to obtain the compound 7a.
Microwave-assisted synthesis.
Using various solvents. An equimolar mixture of 4 and 5a was dissolved in
the minimum amount of an appropriate solvent required to form slurry [(a) ethanol=
concentrated HCl, (b) toluene=glꢀAcOH, (c) ethyl alchohol=concentrated HCl, (d)
ethylene glycol=piperidine, (e) 1,4-dioxane] in an open borosil vessel. It was irradiated
under MW at an appropriate power output for an adequate time (Table 2) until the reac-
tion was completed as indicated by TLC. The reaction mixture was cooled and poured
over crushed ice in the cases of solvents (c) and (d). The crystalline product separated out
immediately on cooling in the cases of (a) and (b). The reaction mixture was cooled and
poured into water in the case of (e). The crystals thus obtained were filtered, dried, and
recrystallized from benzene to obtain the title compound 7a (Table 2).
Using inorganic solid supports in dry media. Equimolar quantities of 4
and 5a were adsorbed separately on montmorillonite KSF and basic alumina (20%
by weight of the reactants) via a solution in ethyl acetate, mixed thoroughly, and irra-
diated for 15 min at 640 W until the completion of the reaction (monitored by TLC).
The recyclable inorganic solid support was separated by filtration after eluting the pro-
duct 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
methods and MW-assisted synthesis prove basic alumina to be the most effective sup-
port. Likewise, the same procedure was followed for the synthesis of compounds 7b–g
and their structural characterization was done on the basis of IR, 1H NMR, mass spec-
tra, and elemental analysis (Tables 3 and 4 and supporting information).
SUPPLEMENTARY DATA
Supplementary data, available online, contains general information, proce-
dures for evaluation of antifungal activity, and spectral data.
ACKNOWLEDGMENTS
We sincerely thank SAIF, Punjab University, Chandigarh for providing micro-
analysis and spectra. The authors are also grateful to the Council of Scientific and
Industrial Research New Delhi, for providing financial support in terms of junior
and senior research fellowships.

3082
D. SINGH ET AL.
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