Activated fly ash catalyzed facile synthesis of novel spiro imidazolidine derivatives as potential antibacterial and antifungal agents

Article abstract of DOI:10.3109/14756366.2010.503611

An array of novel spiro imidazolidine derivatives was synthesized in dry media and was screened for their anti-microbial activities. Structure-activity relationship results revealed that compounds 22, 23 against P.aeruginosa, 24 against S.aureus, 24, 25 against K.pneumonia, 27 against S.aureus, β-H.streptococcus, 29 against M.luteus, K.pneumonia, 29, 30 against P.vulgaris exhibited excellent antibacterial activity at a minimum inhibitory concentration (MIC) value of 6.25 μg/mL. Compound 23 against M.gypseum, 25, 29 against Candida 6 and 29, 30 against C.albicans revealed excellent antifungal activity at a MIC value of 6.25 μg/mL.

Full text of DOI:10.3109/14756366.2010.503611

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011; 26(2): 280–287
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2010.503611
ORIGINAL ARTICLE
Activated fly ash catalyzed facile synthesis of novel spiro
imidazolidine derivatives as potential antibacterial and
antifungal agents
V. Kanagarajan, J. anusu, and M. Gopalakrishnan
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University, Annamalai Nagar-608 002,
Tamil Nadu, India
Abstract
An array of novel spiro imidazolidine derivatives was synthesized in dry media and was screened for their anti-
microbial activities. Structure-activity relationship results revealed that compounds 22, 23 against P.aeruginosa, 24
against S.aureus, 24, 25 against K.pneumonia, 27 against S.aureus, β-H.streptococcus, 29 against M.luteus, K.pneumonia,
29, 30 against P.vulgaris exhibited excellent antibacterial activity at a minimum inhibitory concentration (MIC) value
of 6.25 µg/mL. Compound 23 against M.gypseum, 25, 29 against Candida 6 and 29, 30 against C.albicans revealed
excellent antifungal activity at a MIC value of 6.25 µg/mL.
Keywords: Spiro imidazolidine derivatives, ethylene diamine, activated fly ash, antibacterial activity, antifungal
activity
Introduction
organic synthesis, imidazolidine units are also used as
Fly ash generated during the combustion of coal for en-
ergy production is one of the industrial by product and
it is recognized as an environmental pollutant1. During
the initial stages, only its pozzolanic activity was paid
attention2. Many researchers devoted themselves to the
research of the potential activity of Fly ash and the hydra-
tion process of Fly ash cement3. Activated fly ash was used
to catalyze Knoevenagel condensation, ‘one-pot’ conver-
sions of ketones to amides via, Beckmann rearrange-
ment, Schiff Bases formation, Biginelli, and Hantzsch
reactions4, ‘one-pot’ synthesis of 1,2,4,5-tetrazinanes5,
microwave-assisted, solvent-free alkylation and acyla-
tion of 2-mercaptobenzothiazole6, different ether and
ester derivatives of carvacrol7, liquid phase esterification
of salicylic acid8 with acetic anhydride and methanol
respectively, grindstone chemistry solid-state reaction
procedure for the synthesis of heterocyclic oximes9, and
‘one-pot’ synthesis of pyrimidino thiazolidin-4-ones10.
e importance of imidazolidine unit arises, because they
are found in many biologically active compounds11,12. In
synthetic intermediates13,14, chiral auxiliaries15, chiral ca-
talysis16, and ligands for asymmetric catalysis17. Like imi-
dazole, imidazolidine-based compounds have been used
as N-heterocyclic carbene ligands18 on various transition
metals. It is found in the commercially available second
generation Grubbs’ catalyst. Many imidazolidines are
biologically active. Most bio-active derivatives bear a
substituent (aryl or alkyl group) on the carbon between
the nitrogen centers. Oxymetazoline18 is a selective α-1
agonist and partial α-2 agonist topical decongestant.
Xylometazoline is a drug which is used as a nasal decon-
gestant. Tetrahydrozoline, a derivative of imidazolidine,
is an α-agonist19 and its main mechanism of action is the
constriction of conjunctival blood vessels. is serves
to relieve the redness of the eye caused by minor ocu-
lar irritants. Naphazoline is a sympathomimetic agent20
with marked α-adrenergic activity. Clonidine is used
as a direct-acting α-2 adrenergic agonist. An imidazole
ring is part of some anti-tumor drugs such as dacarba-
zine and imuran21 as well the tumor growth inhibiting
Address for Correspondence: Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University, Annamalai
Nagar-608 002, Tamil Nadu, India. E-mail: profmgk@yahoo.co.in
(Received 14 April 2010; revised 22 June 2010; accepted 22 June 2010)
280

Spiro imidazolidine derivatives as antimicrobial agents 281
cyclocreatine22. Recently, there has been a great deal of
interest in exploiting more than one proximal functional
groups for designing new structures capable of perform-
ing a variety of functions. e present study describes the
use of 6-carbethoxy-3,5-diarylcyclohex-2-enone23 as a
key intermediate with three versative functional groups
i.e., ketone, olefin, and ester for the synthesis of imida-
zolidine derivatives. Owing to our interest in synthesis of
fascinating biologically active hybrid heterocyclic com-
pounds24–26 and as part of our research program, herein
we planned to design a spiro imidazolidine derivatives
bearing a cyclohexene substituent on the carbon be-
tween the nitrogen centers to give a new series of spiro
imidazolidine heterocycles because most bio-active
imidazolidine derivatives bear a substituent (aryl or alkyl
layer was washed with 10% sodium hydrogen carbonate,
brine solution and then excess of water and dried over
anhydrous magnesium sulfate. After evaporation of the
ethyl acetate under vacuum, a solid mass was obtained,
which was subjected to flash column chromatography
using toluene-ethyl acetate as eluent.
Spectroscopic data
7,9-diphenyl-1,4-diazaspiro[4.5]-deca-9-ene-6-ethyl
carboxylate 21
IR (KBr) (cm−1): 3448, 3388, 3175, 3054, 3022, 2972,
2931, 2837, 1738, 1599, 1447, 1027, 827, 758, 698; 1H NMR
(δ ppm): 0.89–0.90 (t, 3H, ester CH3, J= 7.1 Hz); 2.97–3.02
(m, 2H, H8), 3.04–3.22 (m, 1H, H7), 3.51–3.67 (m, 1H, H6),
3.87–3.92 (q, 2H, ester CH2, J= 6.8 Hz), 4.02–4.13 (m, 4H,
group) on the carbon between the nitrogen centers18–21
.
imidazolidine 2CH2), 5.98 (s, 2H, imidazolidine 2NH),
3
6.54 (s, 1H, H10), 7.10–7.79 (m, 10H, Ar-H’s); In the D2O
exchanged 1H NMR spectrum, singlet at 5.98 ppm which
resonates due to 2NH’s of imidazolidine moiety disap-
peared; 13C NMR (δ ppm): 13.7 ester CH3, 35.2 C-7, 43.8
C-8, 49.3 C-2, and C-3, 58.7 ester CH2, 59.9 C-6, 121.9 C-10,
122.88–130.4 Ar-C’s, 137.3, 141.4 ipso-C, 169.2 C=O.
7-(4-chlorophenyl)-9-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 22
Experimental
Chemistry
General remarks
We used thin layer chromatography (TLC) to assess the
progress of the reactions. All the reported melting points
were taken in open capillaries and were uncorrected. IR
spectra were recorded in KBr (pellet forms) on a ermo
Nicolet-Avatar-330 FT-IR spectrophotometer and note
worthy absorption values (cm−1) alone were listed. One-
dimensional 1H and 13C NMR spectra were recorded
at 400 MHz and 100 MHz, respectively on Bruker AMX
400 NMR spectrometer using DMSO-d as solvent. Two
dimensional Heteronuclear Single-Quantum Coherence
(HSQC) spectrum was recorded at 500 MHz on Bruker
DRX 500 NMR spectrometer using DMSO-d as solvent.
e electron spray impact positive (+ve) mass spectra
(MS) were recorded on a Bruker Daltonics liquid chro-
matography-mass spectrometry spectrometer. Satisfac-
tory microanalyses were obtained on Carlo Erba 1106
CHN analyzer. Gyan Ease Flash column chromatography
system, Italy was used for flash column chromatography.
BIOTAGE Initiator microwave synthesizer, Sweden a sci-
entific microwave oven was used for the irradiation.
By adopting the literature procedure, 1,3-diaryl-prop-
2-en-1-ones 1-1027 and 6-carbethoxy-3,5-diarylcyclohex-
2-enone 11-2023 were prepared.
General procedure for the synthesis of 7,9-diaryl-1,4-
diazaspiro[4.5]-deca-9-ene-6-ethyl carboxylates 21-30
In a 10 mL pyrex glass tube were placed respective
6-carbethoxy-3,5-diarylcyclohex-2-enones (0.01 mol),
ethylene diamine (0.01 mol) and catalytic amount of ac-
tivated fly ash (15 mg). e top of glass tube was closed
with teflon cover and it was placed in a teflon outer jacket
and then the reaction tube was placed into the holder in
the microwave cavity. e sample was irradiated under
focused monomode irradiation at 90°C for 4–8 min at 2
bar pressure. After allowing the mixture to cool to room
temperature, the reaction vessel was opened and the
contents were poured into ice cold water. e organic
material was extracted with ethyl acetate. e organic
IR (KBr) (cm−1): 3535, 3437, 3382, 3295, 3065, 2978,
2924, 2847, 1735, 1601, 1445, 1018, 824, 758, 693; 1H NMR
(δ ppm): 0.92–0.93 (t, 3H, ester CH3, J= 7.2 Hz); 2.97–3.07
(m, 2H, H8), 3.10–3.14 (m, 1H, H7), 3.57–3.76 (m, 1H, H6),
3.89–3.94 (q, 2H, ester CH2, J= 6.6 Hz), 4.02–4.15 (m, 4H,
imidazolidine 2CH2), 6.12 (s, 2H, imidazolidine 2NH),
6.55 (s, 1H, H10), 7.13–7.79 (m, 9H, Ar-H’s); In the D2O
exchanged 1H NMR spectrum, singlet at 6.12 ppm which
resonates due to 2NH’s of imidazolidine moiety disap-
peared; 13C NMR (δ ppm): 13.7 ester CH3, 34.9 C-7, 43.1
C-8, 48.4 C-2, and C-3, 58.5 ester CH2, 60.0 C-6, 121.9 C-10,
122.88–140.4 Ar-C’s, 159.1, 160.4 ipso-C, 169.0 C=O.
7-(4-fluorophenyl)-9-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 23
IR (KBr) (cm−1): 3519, 3388, 3262, 3186, 3058, 2977,
2930, 2863, 1739, 1604, 1443, 1023, 832, 758, 694; 1H NMR
(δ ppm): 0.88–0.90 (t, 3H, ester CH3, J= 7.0 Hz); 2.74–2.94
(m, 2H, H8), 2.98–3.13 (m, 1H, H7), 3.56–3.88 (m, 1H, H6),
3.87–3.92 (q, 2H, ester CH2, J= 6.8 Hz), 3.95–4.13 (m, 4H,
imidazolidine 2CH2), 6.02 (s, 2H, imidazolidine 2NH),
6.57 (s, 1H, H10), 6.83–7.94 (m, 9H, Ar-H’s); In the D2O
exchanged 1H NMR spectrum, singlet at 6.02 ppm which
resonates due to 2NH’s of imidazolidine moiety disap-
peared; 13C NMR (δ ppm): 13.7 ester CH3, 35.2 C-7, 42.9
C-8, 48.4 C-2, and C-3, 59.8 ester CH2, 61.0 C-6, 122.3
C-10, 113.1–136.1 Ar-C’s, 157.8, 158.2 ipso-C, 169.1 C=O.
7-(4-methylphenyl)-9-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 24
IR (KBr) (cm−1): 3454, 3399, 3267, 3054, 3038, 2981,
1
2921, 2863, 1739, 1604, 1023, 832, 758, 694; H NMR (δ
ppm): 0.92–0.96 (t, 3H, ester CH3, J= 6.9 Hz); 2.26 (s, 3H,
CH3 of phenyl ring), 2.72–2.93 (m, 2H, H8), 2.97–3.12 (m,
1H, H7), 3.56–3.76 (m, 1H, H6), 3.87–3.93 (q, 2H, ester CH2,
J= 6.6 Hz), 4.00–4.09 (m, 4H, imidazolidine 2CH2), 5.94 (s,
© 2011 Informa UK, Ltd.

282 V. Kanagarajan et al.
2H, imidazolidine 2NH), 6.53 (s, 1H, H10), 6.88–7.91 (m,
9H, Ar-H’s); In the D2O exchanged H NMR spectrum,
CH2, J= 6.9 Hz), 4.00–4.10 (m, 4H, imidazolidine 2CH2),
6.00 (s, 2H, imidazolidine 2NH), 6.55 (s, 1H, H10), 6.89–
7.98 (m, 8H, Ar-H’s); In the D2O exchanged 1H NMR spec-
trum, singlet at 6.00 ppm which resonates due to 2NH’s
of imidazolidine moiety disappeared; 13C NMR (δ ppm):
14.2 ester CH3, 20.5 CH3 of phenyl ring, 35.5 C-7, 43.2 C-8,
48.8 C-2, and C-3, 59.8 ester CH2, 61.0 C-6, 122.2 C-10,
123.2-154.5 Ar-C’s, 157.8, 159.2 ipso-C, 169.0 C=O.
1
singlet at 5.94 ppm which resonates due to 2NH’s of imi-
dazolidine moiety disappeared; 13C NMR (δ ppm): 13.7
ester CH3, 20.5 CH3 of phenyl ring, 35.3 C-7, 43.3 C-8, 48.9
C-2, and C-3, 59.8 ester CH2, 60.9 C-6, 121.9 C-10, 122.8-
138.4 Ar-C’s, 159.2, 160.0 ipso-C, 169.1 C=O.
7-(4-methoxyphenyl)-9-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 25
7-(4-chlorophenyl)-9-(4-methoxyphenyl)-1,4-
diazaspiro[4.5]-deca-9-ene-6-ethyl carboxylate 29
IR (KBr) (cm−1): 3524, 3424, 3267, 3054, 2989, 2929,
1
2830, 1739, 1445, 1607, 1033, 832, 760, 694; H NMR (δ
IR (KBr) (cm−1): 3442, 3393, 3284, 3065, 2962, 2923,
2850, 1738, 1598, 1457, 1140, 826, 718; 1H NMR (δ ppm):
0.92–0.94 (t, 3H, ester CH3, J= 7.3 Hz); 2.77–2.98 (m, 2H,
H8), 2.77–2.98 (m, 1H, H7), 3.48–3.75 (m, 1H, H6), 3.77 (s,
3H, OCH3 of phenyl ring), 3.88–3.93 (q, 2H, ester CH2,
J= 6.7 Hz), 4.01–4.06 (m, 4H, imidazolidine 2CH2), 5.96 (s,
2H, imidazolidine 2NH), 6.55 (s, 1H, H10), 6.96–7.82 (m,
ppm): 0.92–0.94 (t, 3H, ester CH3, J= 7.1 Hz); 2.69–2.93
(m, 2H, H8), 2.97–3.12 (m, 1H, H7), 3.58–3.64 (m, 1H, H6),
3.72 (s, 3H, OCH3 of phenyl ring), 3.88–3.93 (q, 2H, ester
CH2, J= 6.9 Hz), 3.96–4.36 (m, 4H, imidazolidine 2CH2),
5.94 (s, 2H, imidazolidine 2NH), 6.61 (s, 1H, H10), 6.85-
7.78 (m, 9H, Ar-H’s); In the D2O exchanged 1H NMR spec-
trum, singlet at 5.94 ppm which resonates due to 2NH’s
of imidazolidine moiety disappeared; 13C NMR (δ ppm):
13.7 ester CH3, 35.4 C-7, 43.0 C-8, 48.5 C-2 & C-3, 54.9
OCH3 of phenyl ring, 59.8 ester CH2, 60.9 C-6, 121.9 C-10,
113.1-158.2 Ar-C’s, 159.3, 160.6 ipso-C, 169.2 C=O.
1
8H, Ar-H’s); In the D2O exchanged H NMR spectrum,
singlet at 5.96 ppm which resonates due to 2NH’s of imi-
dazolidine moiety disappeared; 13C NMR (δ ppm): 13.7
ester CH3, 36.0 C-7, 43.7 C-8, 49.2 C-2, and C-3, 55.2 OCH3
of phenyl ring, 59.8 ester CH2, 60.9 C-6, 119.9 C-10, 120.9-
158.5 Ar-C’s, 159.6, 161.2 ipso-C, 169.2 C=O.
9-(4-chlorophenyl)-7-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 26
9-(4-chlorophenyl)-7-(4-methoxyphenyl)-1,4-
diazaspiro[4.5]-deca-9-ene-6-ethyl carboxylate 30
IR (KBr) (cm−1): 3453, 3393, 3262, 3065, 2951, 2927,
IR (KBr) (cm−1): 3524, 3386, 3175, 3059, 3029, 2978,
2927, 2858, 1738, 1448, 1584, 1013, 824, 762, 699; 1H NMR
(δ ppm): 0.90–0.91 (t, 3H, ester CH3, J= 7.2 Hz); 2.71–2.97
(m, 2H, H8), 3.00–3.15 (m, 1H, H7), 3.60–3.78 (m, 1H, H6),
3.88–3.93 (q, 2H, ester CH2, J= 6.9 Hz), 3.97–4.13 (m, 4H,
imidazolidine 2CH2), 6.08 (s, 2H, imidazolidine 2NH),
6.59 (s, 1H, H10), 6.88–7.79 (m, 9H, Ar-H’s); In the D2O
exchanged 1H NMR spectrum, singlet at 6.08 ppm which
resonates due to 2NH’s of imidazolidine moiety disap-
peared; 13C NMR (δ ppm): 14.2 ester CH3, 35.1 C-7, 43.0
C-8, 48.3 C-2, and C-3, 59.9 ester CH2, 61.0 C-6, 122.8
C-10, 114.3–137.6 Ar-C’s, 141.4, 159.2 ipso-C, 168.9 C=O.
9-(4-methoxyphenyl)-7-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 27
1
2830, 1738, 1608, 1456, 1032, 824, 749, 711; H NMR (δ
ppm): 0.92–0.94 (t, 3H, ester CH3, J= 7.2 Hz); 2.87–3.09 (m,
2H, H8), 3.12–3.19 (m, 1H, H7), 3.59–3.70 (m, 1H, H6), 3.71
(s, 3H, OCH3 of phenyl ring), 3.87–3.92 (q, 2H, ester CH2,
J= 6.7 Hz), 4.05–4.20 (m, 4H, imidazolidine 2CH2), 5.96 (s,
2H, imidazolidine 2NH), 6.55 (s, 1H, H10), 7.24–7.91 (m,
1
8H, Ar-H’s); In the D2O exchanged H NMR spectrum,
singlet at 5.96 ppm which resonates due to 2NH’s of imi-
dazolidine moiety disappeared; 13C NMR (δ ppm): 14.3
ester CH3, 35.6 C-7, 43.1 C-8, 48.4 C-2, and C-3, 55.2 OCH3
of phenyl ring, 59.9 ester CH2, 61.0 C-6, 119.9 C-10, 120.9-
158.4 Ar-C’s, 159.7, 161.2 ipso-C, 169.1 C=O.
IR (KBr) (cm−1): 3450, 3444, 3065, 3033, 2924, 2852,
1736, 1605, 1447, 1037, 757, 695; 1H NMR (δ ppm): 0.90–
0.92 (t, 3H, ester CH3, J= 7.0 Hz); 2.72–2.98 (m, 2H, H8),
3.01–3.16 (m, 1H, H7), 3.59–3.71 (m, 1H, H6), 3.73 (s, 3H,
OCH3 of phenyl ring), 3.88–3.93 (q, 2H, ester CH2, J= 6.8
Hz), 3.96–4.08 (m, 4H, imidazolidine 2CH2), 5.93 (s, 2H,
imidazolidine 2NH), 6.51 (s, 1H, H10), 6.83–7.81 (m, 9H,
Ar-H’s); In the D2O exchanged 1H NMR spectrum, singlet
at 5.93 ppm which resonates due to 2NH’s of imidazoli-
dine moiety disappeared; 13C NMR (δ ppm): 13.7 ester
CH3, 36.0 C-7, 43.7 C-8, 49.2 C-2, and C-3, 54.3 OCH3 of
phenyl ring, 59.9 ester CH2, 61.0 C-6, 122.3 C-10, 116.2-
141.4 Ar-C’s, 157.8, 159.2 ipso-C, 169.0 C=O.
Microbiology
Materials
All the clinically isolated bacterial strains namely Staphy-
lococcus aureus, β-Haemolytic streptococcus, Micrococ-
cus luteus, Pseudomonas aeruginosa, Proteus vulgaris,
Klebsiella pneumonia and fungal strains namely Candida
albicans, Candida 6, Candida 51, Candida neoformans
and Microsporum gypsuem were obtained from Faculty
of Medicine, Annamalai University, Annamalainagar-608
002, Tamil Nadu, India.
In vitro antibacterial and antifungal activity
9-(4-chlorophenyl)-7-(4-methylphenyl)-1,4-
diazaspiro[4.5]-deca-9-ene-6-ethyl carboxylate 28
IR (KBr) (cm−1): 3459, 3386, 3273, 3169, 3049, 2983,
2923, 2856, 1739, 1612, 1447, 1013, 817, 744, 711; 1H NMR
(δ ppm): 0.92–0.94 (t, 3H, ester CH3, J= 7.1 Hz); 2.27 (s,
3H, CH3 of phenyl ring), 2.75–2.98 (m, 2H, H8), 2.98–3.15
(m, 1H, H7), 3.57–3.77 (m, 1H, H6), 3.87–3.93 (q, 2H, ester
Minimum inhibitory concentration (MIC) in μg/mL val-
ues was carried out by twofold serial dilution method28.
e respective test compounds 21-30 were dissolved in
dimethylsulphoxide (DMSO) to obtain 1 mg/mL stock so-
lution. Seeded broth (broth containing microbial spores)
was prepared in NB from 24 h old bacterial cultures on
nutrient agar (Hi-media, Mumbai) at 37 1°C whereas
Journal of Enzyme Inhibition and Medicinal Chemistry

Spiro imidazolidine derivatives as antimicrobial agents 283
fungal spores from 1 to 7 days old Sabourauds agar (Hi-
media, Mumbai) slant cultures were suspended in Sab-
ourauds dextrose broth (SDB). e colony forming units
(cfu) of the seeded broth were determined by plating
technique and adjusted in the range of 104–105 cfu/mL.
e final inoculums size was 105 cfu/mL for antibacterial
assay and 1.1–1.5 × 102 cfu/mL for antifungal assay. Test-
ing was performed at pH 7.4 0.2 for bacteria (NB) and
at a pH 5.6 for fungi (SDB). Exactly 0.4 mL of the solution
of test compound was added to 1.6 mL of seeded broth to
form the first dilution; 1 mL of this was diluted with a fur-
ther 1 mL of seeded broth to give the second dilution and
so on till six such dilutions were obtained. A set of assay
tubes containing only seeded broth was kept as control.
e tubes were incubated in BOD incubators at 37 1°C
for bacteria and 28 1°C for fungi. MICs were recorded by
visual observations after 24 h (for bacteria) and 72–96h
(for fungi) of incubation. Penicillin was used as standard
for bacterial studies and Amphotericin B was used as
standard for fungal studies.
was able to reach a temperature of 135°C after 6min of
irradiation in domestic oven. (p= 320 W). e reagent can
be stored in a vacuum desiccator.
Facile synthesis of novel imidazolidine derivatives
was carried out by the reaction of 6-carbethoxy-3,5-
diarylcyclohex-2-enones 11-20 with ethylene diamine
in the presence of activated fly ash in dry media under
scientific focused MWI, because the applications of
microwave technology to rapid synthesis of biologically
significant heterocyclic molecules under solvent-free
conditions are very promising and numerous and has re-
cently been recognized as a useful tool for a drug-discov-
ery program especially in combinatorial chemistry. e
reactions were performed at 90°C and two bar pressure
for 4–8 min. After completion of the reaction as indicated
by the TLC, the reaction mixture was poured into ice wa-
ter. e mixture was extracted with dichloromethane and
washed with 10% sodium bicarbonate solution, finally
washed with distilled water, concentrated in rotary evap-
orator and purified by flash column chromatography us-
ing toluene:ethyl acetate (1:1) as eluent.
e synthetic route for the formation of target mol-
ecules 21-30 was given in Scheme 1. e physical and
analytical data was given in Table 1. e structures of
all the synthesized compounds 21-30 are discussed
with the help of m.p.’s, elemental analysis, FT-IR, MS,
one-dimensional 1H NMR, D2O exchanged 1H NMR,
13C NMR and two dimensional HSQC spectra. In order
to investigate the spectral assignments, new imida-
zolidine derivative, 7-(4-fluorophenyl)-9-phenyl-1,4-
diazaspiro[4.5]-deca-9-ene-6-ethyl carboxylate 23 was
chosen as a representative compound. FT-IR spectrum
Results and discussion
Several methods have been reported for the synthesis
of imidazolidines29–35 which include conversion of es-
ters using aluminium reagents29, the reaction between
N-ethoxy carbonylthioamides with 1,2-diamines30 and
the reaction of aldehydes with 1,2-diamines followed by
N-halosuccinimides31. Recently, several method have
been developed where azalactones32, 2-aryl-1, 1-dibro-
moethanes33, nitriles34 and amino amides35 are used as
starting material for this synthesis. However, many of
the synthesis protocols reported so far suffer from dis-
advantages such as needing anhydrous conditions29,
use of organic solvents29–35, harsh reaction conditions29,
prolonged reaction time31, use of metals and expensive
reagents29 etc., erefore the development of an alterna-
tive cost effective, safe and environment friendly reagent
system is attractive. In continuation of our earlier interest
in synthesizing variety of organic molecules of industrial
and pharmacological interest, we attempted and suc-
ceeded to synthesize a series of imidazolidine derivatives
catalyzed by activated fly ash under microwave irradia-
tion (MWI).
e Fly ash as-received was sieved in a 100 mesh sieve
to remove any coarser and foreign particles and then
mechanically ground in a ball mill to fine powder. e
particle size distribution was found to be between 40 and
90 μm. Finely ground Fly ash was kept at a temperature
of about 900–1000°C in a silica crucible for 1h for activa-
tion and was used for investigation. e carbon, sulphur,
and other impurities were removed by thermal activation
and the resultant Fly ash is called Activated Fly ash4. e
chemical compositions of fly ash4 was SiO2 (64.03%), Al2O3
(15.50%), Fe2O3 (6.50%), CaO (4.62%), MgO (3.00%), loss
on ignition (4.35%), insoluble residue (2.00%). Activated
Fly ash was shown to be one of the most efficient MW
absorbers with a very high specificity to MW heating. It
of
7-(4-fluorophenyl)-9-phenyl-1,4-diazaspiro[4.5]-
deca-9-ene-6-ethyl carboxylate 23 shows characteristic
absorption frequencies at 3519, 3388, and 3262 cm−1
suggests the presence of NH stretching frequency. e
absorption frequency at 1739 cm−1 is due to the presence
of carbonyl stretching of ester group. Moreover, the ab-
sorption frequency at 1604 cm−1 is due to the presence of
C=C stretching. e presence of band at 1443cm−1 (C-N)
is more evident for the formation of 23. e observed NH
stretching, C=C stretching, C=0 of ester functional group
absorption bands, all support evidence for the formation
of compound 23. e mass spectrum of 23 shows molec-
ular ion peak at m/z 381(M+•+1) which is consistent with
the proposed molecular formula, C23H25N2O2F. Elemental
analysis [Ccal 72.61, Cobs 72.52; Hcal 76.62, Hobs 6.57; Ncal
7.36, Nobs 7.23] is consistent with the proposed molecular
formula [C23H25N2O2F] of 23.
e assignments of signals in 1H NMR spectrum of 23
have been done based on total widths, position, and spin
multiplicities. A singlet observed at 6.57 ppm is conve-
niently assigned to H10 proton of cyclohexene moiety.
Two multiplets appeared in the region of 2.74–2.94 ppm
is due to methylene protons H8 of cyclohexene moiety.
Another multiplet observed in the range 2.98–3.13 ppm
is due to benzylic proton H7. e methyl protons (CH3)
of ester group appear as a triplet, centered at 0.89 ppm.
© 2011 Informa UK, Ltd.

284 V. Kanagarajan et al.
X
Y
O
H
H3C
O
NaOH
20ºC,1h
stirring
+
EtOH
(1-10)
O
O
O
Y
NaOEt
EtOH
reflux, 2h
X
O
CH3
O
H2N
2
3
NH2
O
O
1
4
HN
NH
Activated Fly ash
5
MW
2bar, 90ºC
4-8min.
O
O
10
9
6
7
8
(21-30)
(11-20)
X
Y
X
Y
Scheme 1. Fly ash catalyzed facile synthesis of novel spiro imidazolidine derivatives under microwave irradiation.
Table 1. Physical and analytical data for the title compounds 21-30.
Elemental analysis (%)
C Found
H Found
N Found m/z (M+1)+•Molecular
formula
Compounds
X
Y
m.p.(° C) MW Time (min) Yield (%) (calculated) (calculated) (calculated)
21
22
23
24
25
26
27
28
29
30
H
H
77
100
65
6
8
4
5
8
7
6
4
6
8
95
93
98
90
88
91
90
93
90
90
76.11 (76.21) 7.15 (7.23) 7.63 (7.73) 363 C23H26N2O2
69.48 (69.60) 6.24 (6.35) 6.95 (7.06) 397 C23H25N2O2Cl
72.52 (72.61) 6.57 (6.62) 7.23 (7.36) 381 C23H25N2O2F
76.49 (76.56) 7.43 (7.50) 7.32 (7.44) 377 C24H28N2O2
73.33 (73.44) 7.10 (7.19) 7.01 (7.14) 393 C24H28N2O3
69.52 (69.60) 6.30 (6.35) 6.97 (7.06) 397 C23H25N2O2Cl
73.32 (73.44) 7.11 (7.19) 7.03 (7.14) 393 C24H28N2O3
70.04 (70.15) 6.53 (6.62) 6.78 (6.82) 411 C24H27N2O2Cl
67.42 (67.52) 6.25 (6.37) 6.51 (6.56) 427 C24H27N2O3Cl
67.44 (67.52) 6.29 (6.37) 6.48 (6.56) 427 C24H27N2O3Cl
H
Cl
H
F
H
CH3
OCH3
H
117
112
68
H
Cl
OCH3
Cl
H
65
CH3
73
OCH3 Cl
Cl OCH3
69
99
e methylene protons (CH2) of ester group observed
as a quartet, centered at 3.90 ppm. A signal observed as
multiplet at around 3.56–3.88 ppm corresponding to one
proton is unambiguously assigned to H6 proton. e
two NH protons of imidazolidine moiety were appeared
as broad singlet at 6.02 ppm corresponding to two pro-
tons. In addition, methylene protons (H-2, H-3) at C-2
and C-3 of imidazole moiety observed as a multiplet at
around 3.95–4.13 ppm. e aromatic protons appear as
a multiplet in the range 6.83–7.94 ppm. e presence of
labile-NH protons at positions one and four is confirmed
by recording the 1H NMR spectrum after adding D2O. e
peak at 6.02 ppm due to 2 NH’s protons at position 1 and
4 have disappeared in the D2O exchanged 1H NMR spec-
trum. In 13C NMR spectrum of 23 six resonances in the
aliphatic region 13.7, 59.8, 48.4, 59.8, 35.2, and 42.9 ppm
have been observed. (with the help of HSQC the indi-
vidual assignment could be carried out). e remaining
13C resonances at 169.1, 157.8, and 158.2 ppm are due to
quaternary carbons. e 13C resonance at 122.3 ppm may
be due to C-10 carbon. Aromatic carbons are observed in
the range of 113.1–136.1 ppm.
In the HSQC spectrum of 23, the one bond correlation
(13.7/0.90 ppm) between methyl protons and methyl
carbon of ester confirms that signal observed at 0.90 ppm
must be due to methyl protons of ester and 13C resonance
at 13.7 ppm must be assigned to methyl carbon of ester.
A multiplet observed in the region of 2.74–2.94 ppm is
assigned to methylene protons H8. Because H8 pro-
ton is assigned from HSQC spectrum, the cross peak
(42.9/2.74–2.94 ppm) confirms that the 13C resonance at
42.9 ppm is due to C-8 carbon. In HSQC, the 13C reso-
nances at 35.2 ppm has correlations with benzylic proton
H7 (35.2/2.98–3.13ppm) hence C-7 resonates at 35.2 ppm
and multiplet observed at around 2.98–3.13 ppm must be
due to benzylic proton H7. In HSQC the 13C resonances
at 59.8 ppm has correlations with the methylene protons
of ester group (59.8/3.89 ppm) and hence methylene
Journal of Enzyme Inhibition and Medicinal Chemistry

Spiro imidazolidine derivatives as antimicrobial agents 285
carbon of ester resonates at 59.8 ppm. e 13C resonance
at 122.3 ppm shows cross peak (122.3/6.57 ppm) with
H10 proton and hence that resonance has been as-
signed to C-10. e 13C resonance at 61.0 ppm has cross
peak (61.0/3.56–3.88 ppm) in HSQC with methine pro-
ton signal (H6). Hence the resonance at 61.0 ppm must
be due to C-6 carbon. Moreover, the 13C resonance at
48.4 ppm has correlation with a multiplet observed in
range 3.95–4.13 ppm (48.4/3.95–4.13 ppm). e multip-
let observed at around 3.95–4.13 ppm is unambiguously
assigned to methylene protons at C-2 and C-3. e cross
peaks (48.4/3.95–4.13 ppm) confirm that 13C resonances
at 48.4 ppm must be due to methylene carbons at C-2 and
C-3 of imidazole moiety. In HSQC, the 13C resonances at
80.2, 157.8, 158.2, and 169.1 ppm have no correlations
with protons. Among the carbon resonances, the 13C
resonances at 169.1 ppm must be due to carbonyl carbon
of ester and 13C resonance at 80.2 ppm is due to spiro
carbon (C-5). e 13C resonances at 157.8 and 158.2 ppm
are assigned to ipso carbons. e C-9 carbon resonance is
merged with the aromatic region (157.8 and 158.2 ppm).
of chloro substitution by methoxy substitution at the
para position of phenyl ring attached to C-9 of cyclo-
hexene moiety exhibit tremendous antibacterial activity
against S.aureus and β-H.streptococcus at a MIC value of
6.25 µg/mL. Compound 28, which have both electron
withdrawing chloro substitution at the para position
of phenyl ring attached to C-9 and electron donating
methyl substitution at the para position of phenyl ring
attached to C-7 position of cyclohexene moiety exhibit
good activity against P.aeruginosa and K.pneumonia at a
MIC value of 12.5 µg/mL. Likewise, compound 29 which
have electron donating methoxy substitution at the para
position of phenyl ring attached to C-9 position and elec-
tron withdrawing chloro substitution at the para position
of phenyl ring attached to C-7 of cyclohexene moiety
possess tremendous activity against M.luteus, P.vulgaris,
and K.pneumonia at a MIC value of 6.25 µg/mL. Com-
pound 30, which have both electron withdrawing chloro
substitution at the para position of phenyl ring attached
to C-9 and electron donating methoxy substitution at the
para position of phenyl ring attached to C-7 position of
cyclohexene moiety exhibit good activity against β-H.
streptococcus and M.luteus and exerted excellent activity
against P.vulgaris at a MIC value of 12.5 µg/mL.
In vitro antibacterial activity
Novel spiro imidazolidine derivatives 21-30 are tested
for their in vitro antibacterial activity against S.aureus,
β-H.streptococcus, M.luteus, P.aeruginosa, P.vulgaris,
and K.pneumonia. Penicillin is used as standard drug.
MIC in μg/mL values is reproduced in Table 2. Among
the compounds tested, compound 21 which is having
no substitution at the para position of phenyl rings at-
tached to C-7 and C-9 carbons of cyclohexene moiety
exerted moderate activities against all the used bacterial
strains. All the synthesized compounds 21-30 exhibit a
wide range of antibacterial potency against the tested
strains except compounds 21 and 26 which did not show
activity against β-H.streptococcus and M.luteus even at
a higher concentration of 200 µg/mL. Structure-activity
relationship results for the synthesized compounds have
shown that compounds 22 and 23 which are having elec-
tron withdrawing chloro/fluoro substitution at the para
position of phenyl ring attached to C-7 of cyclohexene
moiety, respectively show excellent antibacterial activ-
ity against P.aeruginosa at a MIC value of 6.25 µg/mL.
Compound 24, which is having electron donating methyl
substitution at the para position of phenyl ring attached
to C-7 of cyclohexene moiety respectively show excellent
antibacterial activity against S.aureus and K.pneumonia
at a MIC value of 6.25 µg/mL. Compound 25, which
has electron donating methoxy substitution at the para
position of phenyl ring attached to C-7 of cyclohexene
moiety exerted good activites against S.aureus, M.luteus,
and P.vulgaris at a MIC value of 12.5 µg/mL, whereas it
exhibit excellent activity against K.pneumonia at a MIC
value of 6.25 µg/mL. Besides these, compound 26, which
has electron withdrawing chloro substitution at the para
position of phenyl ring attached to C-9 of cyclohexene
moiety show admirable antibacterial activity against
P.aeruginosa at a MIC value of 12.5 µg/mL. Replacement
In vitro antifungal activity
In vitro antifungal activity of compounds 21-30 is
studied against the fungal strains viz., Candida albi-
cans, Candida 6, Candida 51, Candida neoformans,
and Microsporum gypsuem. Amphotericin B is used as
a standard drug. MIC in μg/mL values is reproduced in
Table 3. Compounds 21-30, irrespective of the nature
of functional group electron donating (CH3/ OCH3))
or (electron withdrawing (F/Cl) at the phenyl rings
exerted moderate in vitro antifungal activity against
all the tested fungal strains in the range of 6.25–200
µg/mL except compounds 21, and 27 which do not
show any activity against the tested fungal strains
namely M.gypseum and compounds 22 and 26 against
C.albicans even at a higher concentration of 200 µg/
mL. Compounds 22 and 24 possess good antifungal ac-
tivity against M.gypseum and Candida 51, respectively
at a MIC value of 12.5 µg/mL. Fluoro substituted com-
pound 23 shows excellent antifungal activity against
M.gypseum at a MIC value of 6.25 µg/ mL. Methoxy
substituted compound 25 exhibits good activity against
C.albicans and C.neoformans at a MIC value of 12.5
µg/mL, whereas it show tremendous activity against
Candida 6 at a MIC value of 6.25 µg/ mL. Compound
26 show moderate activity against all the tested fungal
strains except against M.gypseum, which shows activ-
ity at a MIC value of 12.5 µg/mL. Compound 27 possess
good activity against C.albicans and Candida 6 at a MIC
value of 12.5 µg/mL, whereas compound 28 exerted
good activity against C.albicans and Candida 51 at a
MIC value of 12.5 µg/mL and it shows excellent activ-
ity against C.neoformans at a MIC value of 6.25 µg/mL.
Good antifungal activity is exhibited by compound 29
© 2011 Informa UK, Ltd.

286 V. Kanagarajan et al.
Table 2. In vitro antibacterial activity of compounds 21-30 against clinically isolated bacterial strains.
Minimum inhibitory concentration (MIC) in µg/mL
Compounds
X
Y
S.aureus
100
β-Haemolytic streptococcus
M.luteus
200
100
50
P.aeruginosa
P.vulgaris
100
50
K.pneumonia
21
22
23
24
25
26
27
28
H
H
‘-‘
100
50
50
6.25
6.25
200
200
12.5
100
12.5
25
200
25
H
Cl
200
H
F
100
50
25
H
CH3
OCH3
H
6.25
12.5
100
12.5
50
25
25
6.25
6.25
50
H
12.5
‘-‘
12.5
200
50
Cl
50
OCH3
Cl
H
6.25
100
6.25
25
50
200
12.5
6.25
25
CH3
Cl
50
25
29
30
OCH3
Cl
12.5
25
25
6.25
12.5
50
6.25
6.25
50
OCH3
12.5
25
50
Penicillin
25
25
25
‘-‘ No inhibition even at a higher concentration of 200 µg/mL.
Table 3. In vitro antifungal activity of compounds 21-30 against clinically isolated fungal strains.
Minimum inhibitory concentration (MIC) in µg/mL
Compound
X
Y
C.albicans
100
Candida 6
200
Candida 51
Candida neoformans
M.gypsuem
‘-‘
21
22
23
24
25
26
27
28
H
H
100
50
100
200
50
H
Cl
‘-‘
200
12.5
6.25
50
H
F
200
100
200
12.5
25
H
CH3
OCH3
H
25
25
25
H
12.5
‘-‘
6.25
200
12.5
200
25
25
Cl
25
12.5
‘-‘
OCH3
Cl
H
12.5
12.5
6.25
6.25
25
12.5
25
25
CH3
Cl
12.5
25
6.25
12.5
100
50
50
29
30
OCH3
Cl
6.25
12.5
50
12.5
12.5
25
OCH3
50
Amphotericin B
25
‘-‘ No inhibition even at a higher concentration of 200 µg/mL.
against C.neoformans and M.gypseum and compound
30 exhibit activity against Candida 6 and M.gypseum
at a MIC value of 12.5 µg/ mL. In addition, excellent
antifungal activity is noted against C.albicans and
Candida 6 by compound 29 and against C.albicans by
compound 30 at a MIC value of 6.25 µg/ mL.
K.pneumonia, 29, 30 against P.vulgaris exhibited excel-
lent antibacterial activity at a MIC value of 6.25 µg/mL.
Results of the antifungal activity study show that the na-
ture of substituents on the phenyl ring viz., fluoro, chloro,
methyl, methoxy, functions at the para positions of the
aryl ring of cyclohexane moieties are determinant for the
nature and extent of the antifungal activity of all the syn-
thesized compounds 19-27 over all fungal strains. Com-
pound 23 against M.gypseum, 25 against Candida 6, 29
against Candida 6 and 29, 30 against C.albicans revealed
excellent antifungal activity at a MIC value of 6.25 µg/mL.
ese observations may promote a further development
of our research in this field. Further development of this
group of novel spiro imidazolidine derivatives may lead
to compounds with better pharmacological profile than
standard antibacterial and antifungal drugs.
Conclusion
An array of novel spiro imidazolidine derivatives are
synthesized by in the presence of activated fly ash in dry
media under scientific MWI and the structures of the
products are characterized by melting point, elemental
analysis, MS, FT-IR, one-dimensional NMR (1H, D2O ex-
1
changed H & 13C) and two dimensional Heteronuclear
Single Quantum Coherence (HSQC) spectroscopic data.
In addition, the title compounds are screened for their
anti-microbial activities against a spectrum of clinically
isolated antibacterial and antifungal strains. e micro-
biological screening studies carried out to evaluate the
antibacterial and antifungal potencies of the novel spiro
imidazolidine derivatives 21-30 are clearly known from
Table 2 and Table 3. Structure-activity relationship results
revealed that compounds 22, 23 against P.aeruginosa,
24 against S.aureus, 24, 25 against K.pneumonia, 27
against S.aureus, β-H.streptococcus, 29 against M.luteus,
Acknowledgements
Authors are thankful to NMR Research Centre, Indian
Institute of Science, Bangalore for recording spectra.
Declaration of interest
One of the authors namely V.Kanagarajan is grateful to
Council of Scientific and Industrial Research (CSIR), New
Journal of Enzyme Inhibition and Medicinal Chemistry

Spiro imidazolidine derivatives as antimicrobial agents 287
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