Synthesis and In Vitro Study of Hybrid Heterocyclic's as Potential Nematicidal Agents

Article abstract of DOI:10.1002/jhet.2943

A series of novel 5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-6-phenyl-3,3a,5,6-tetrahydroisoxazolo[3,4-d]thiazoles 10a–g were synthesized by the reaction of chalcone derivatives of 2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-phenylthiazolidin-4-one 9 with hydroxylamine hydrochloride. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds 10 a–g were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans; compound 10e and 10f showed appreciable nematicidal activity. Further, the compounds 10a – g were screened for their antifungal activity against Candida albicans (ATCC 10231), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichopyton mentagrophytes (IFO 40996). The compounds 10b and 10f displayed notable antifungal activity against all the microorganisms employed. The activity of these compounds is almost equal to the standard. It is also interesting to note that the compounds 10b and 10f and 10g showed activity towards C. albicans at the concentration of 3.75?μM, which is less than the concentration of the standard Amphotericin B.

Full text of DOI:10.1002/jhet.2943

Month 2017
A. Srinivas,
Synthesis and In Vitro Study of Hybrid Heterocyclic’s as Potential
Nematicidal Agents
M. Sunitha,a P. Karthik,a G. Nikitha,a K. Raju,a B. Ravinder,a S. Anusha,a T. Rajasri,a D. Swapna,a
a
*
D. Swaroopa,a K. Srinivas,a and K. Vasumathi Reddyb
aDepartment of Chemistry, Vaagdevi Degree and PG College, Kishanpura, Warangal, Telangana 506001, India
bDepartment of Zoology, Vaagdevi Degree and PG College, Kishanpura, Warangal, Telangana 506001, India
*
E-mail: avula.sathwikreddy@gmail.com
Received January 18, 2017
DOI 10.1002/jhet.2943
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A
series of novel 5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-6-phenyl-3,3a,5,6-tetrahydroisoxazolo
[3,4-d]thiazoles 10a–g were synthesized by the reaction of chalcone derivatives of 2-((3aR,5S,6S,6aR)-
6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-3-phenylthiazolidin-4-one 9 with hydroxylamine hydrochloride. The chemical structures of newly
synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds
10 a–g were evaluated for their nematicidal activity against Dietylenchus myceliophagus and
Caenorhabditis elegans; compound 10e and 10f showed appreciable nematicidal activity. Further,
the compounds 10a – g were screened for their antifungal activity against Candida albicans (ATCC
10231), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichopyton
mentagrophytes (IFO 40996). The compounds 10b and 10f displayed notable antifungal activity
against all the microorganisms employed. The activity of these compounds is almost equal to the
standard. It is also interesting to note that the compounds 10b and 10f and 10g showed activity
towards C. albicans at the concentration of 3.75 μM, which is less than the concentration of the
standard Amphotericin B.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
aza heterocyclics rank the most potent glycosidase
inhibitors [2]. Further, this nucleus in combination with
or in linking with various other classes of compounds
such as amino acids, steroids, aromatic compounds, and
carbohydrates became prominent in having various
pharmacological properties [3]. 1,2,3-Triazole modified
carbohydrates have became easily available after the
discovery of the Cu(I) catalyzed azide-alkynes 1,3-dipolar
1,2,3-Triazoles are one of the most important classes of
heterocyclic organic compounds, which are reported to be
present in a plethora of biological activities for diverse
therapeutic areas [1]. The 1,2,3-triazole motif is
associated with diverse pharmacological activities such as
antibacterial, antifungal, hypoglycemic, antihypertensive,
and analgesic properties. Polysubstituted five-membered
cycloaddition reaction [4] and quickly became
a
© 2017 Wiley Periodicals, Inc.

A. Srinivas, M. Sunitha, P. Karthik, G. Nikitha, K. Raju, B. Ravinder, S. Anusha,
T. Rajasri, D. Swapna, D. Swaroopa, K. Srinivas, and K. Vasumathi Reddy
Vol 000
prominent class of non-natural sugars. The chemistry and
biology of triazole modified sugars are dominated by
Triazole glycosides [5]. Therefore, the synthesis and
investigation of biological activity of 1,2,3-triazole
glycosides are important objectives, which also received
considerable attention by medicinal chemists.
toxic Aldicarb used to control insects and nematodes
has been detected in ground water [38]. Therefore,
alternative nematode control methods or less toxic
nematicides need to be developed [39]. One way of
searching for such nematicidal compounds is to screen
naturally occurring compounds in plants. Several such
compounds, e.g. alkaloids, phenols, sesquiterpenes,
diterpenes, polyacetylenes, and thienyl derivatives, have
nematicidal activity [40]. For example, α-terthienyl is a
highly effective nematicidal compound [41]. Other
compounds with nematicidal activity have been isolated
from plants, mainly from the family Asteraceae [40].
However, compounds of plant origin and their analogs
have not been developed into commercial nematicides;
hence, there is a need to develop commercial synthesis.
Following the successful introduction of antimicrobial
and nematicidal agents, inspired by the biological profile
of triazoles, thiazolidinones, isoxazoles, and their
increasing importance in pharmaceutical and biological
fields and in continuation of our work on biological
active molecules [42–55] and in order to enhance the
biological activity of triazoles, thiazolidinones and
isoxazoles moieties, it was thought to interest to
accommodate triazole, thiazolidinones, and isoxazoles
moieties in single molecular framework. In this article,
we wish to report the synthesis of a new class of hybrid
heterocyclics 10a–g in good yields and their evaluated in
vitro antifungal and nematicidal activity.
Thiazoles are familiar group of heterocyclic compounds
possessing a wide variety of biological activities, and their
utility as medicine is very much established [6]. Thiazole
nucleus is also an integral part of all the available
penicillins which have revolutionized the therapy of
bacterial diseases [7]. Further, the chemistry of
thiazolidenone ring system is one considerable interest as
it is a core structure in various synthetic pharmaceuticals
displaying a broad spectrum of biological activities [8].
The thiazolidenone nucleus also appears frequently in the
structure of various natural products notably thiamine,
compounds possessing cardiac and glycemic benefits
such as troglitazone [9], and many metabolic products of
fungi and primitive marine animals, including
2-(aminoalyl)-thiazole-4-carboxylic acids [10]. Numerous
thiazolidenone derivatives have shown significant bio
activities such as antidiarrhoeal [11], anticonvulsant [12],
antimicrobial [13], antidiabetic [14], antihistaminic [15],
anticancer [16], anti HIV [17], Ca +2 channel blocker [18],
PAF antagonist [19], cardioprotective [20], antiischemic
[21], COX inhibitory [22], antiplatelet activating factor
[23], non-peptide thrombin receptor antagonist [24],
tumor necrosis factor-α antagonist [25], and nematicidal
activities. Moreover, isoxazole derivatives are an
important class of bio active molecules, which exhibit
significant activities such as anti fungal [26], Aβ precursor
protein [27], protein thyrosine phosphatase 1B inhibitors
[28], antiviral [29], antihelmintics [30], anti inflammatory
[31], anticonvulsant [32], insecticidal [33], antitubercular
[34], immunomodulatory [35], and hypolipermics [36].
Nematodes are tiny worms, some of them are plant
parasites, and can play an important role in the
predisposition of the host plant to the invasion by
secondary pathogens [37]. Plants attacked by nematodes
show retarded growth and development, as well as loss in
the quality and quantity of the harvest. The nematicide
use is slated for reduction due to environmental problems,
and human and animal health concern. For example,
effective nematicides such as dibromochloropropane
(DBCD) and ethylene dibromide (EDB) have been
withdrawn from the market due to their deleterious effects
on human and the environment. Methyl bromide, the most
effective and widely used fumigant for soil borne pests
including nematodes, has already been banned.
RESULTS AND DISCUSSION
The key intermediate, 8, required for the synthesis of
title compound was prepared according to the procedure
outlined in the Scheme 1. Di acetone D-glucose (1)
prepared from D (+)-glucose by treating with acetone in
the presence of catalytic amount of sulfuric acid
according to the literature procedure [56], reduction of 2
prepared by Swern oxidation of 1, with NaBH4 in aq.
ethanol at 0°C for 1 h gave 3 (77%), which on
subsequent propargylation in DMF in the presence of
NaH for 1 h afforded propargyl ether 4 (80%). Now, the
propargyl ether converted into triazole 5 (82%) by using
1,3-dipolar cycloaddition with p-chloro phenyl azide was
4carried out at ambient temperature in the presence of
CuSO4 and sodium ascorbate in a mixture of 1:1 t-
BuOH–H2O as reported by Sharpless. Acid hydrolysis
of 5,6 acetonide 5 in 60% AcOH furnished the diol 6
(85%), which on oxidative cleavage with NaIO4 gave
the aldehyde 7. Subsequently, one-pot synthesis of
triazole linked thiazolidenone glycosides was carried out
by the condensation reaction between 7, primary
aromatic amine and a thio glycolic acid in the presence
of ZnCl2 under microwave irradiation/conventional
The use of nonfumigant nematicides, based on
organophosphates and carbamates, is expected to increase
the withdrawal of methyl bromide, which will bring
about new environmental concerns. In fact, the highly
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis
Scheme 1. Synthesis of compound 7.
heating (Scheme 2). In classical method, the reactions
were performed in dry toluene at reflux for a long time
(2–4 h), often leading to degradation processes and
consequent low yields of isolated products, whereas with
the application of microwave-assisted technology, the
reaction is completed in only 5–10 min, and the
compounds, isolated by conventional workup, are
obtained in satisfactory yields, often higher than those
achieved by traditional methods [42]. Compound 8 was
then reacted with p-fluorobenzaldehyde in the presence
of anhydrous NaOAc in glacial AcOH at reflux
temperature gave chalcone derivatives of triazole linked
thiazolidenone glycosides 9. Compound
9
on
cyclocondensation with hydroxyl amine hydrochloride in
the presence of anhydrous NaOAc in glacial AcOH at
reflux temperature gave Compound 10. The structures of
synthesized compounds were confirmed by IR, NMR,
MS, and elemental analysis. Further, the compounds
were subject to nematicidal and antibacterial testing.
Antifungal activity.
The newly prepared compounds
10a–g were screened for their antifungal activity against
four fungal organisms viz Candida albicans (ATCC
10231), Aspergillus fumigates (HIC 6094), Trichophyton
rubrum (IFO 9185), and Trichophyton mentagrophytes
Scheme 2. Synthesis of compound 10a–g. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Srinivas, M. Sunitha, P. Karthik, G. Nikitha, K. Raju, B. Ravinder, S. Anusha,
T. Rajasri, D. Swapna, D. Swaroopa, K. Srinivas, and K. Vasumathi Reddy
Vol 000
(IFO 40996) by the broth dilution method, recommended
showed moderate activity. The LD
values of the test
50
by the National Committee for Clinical Laboratory
Standards (NCCLS) [57]. The antifungal activity of each
compound was compared with the standard drug
Amphotericin B. Minimum inhibitory concentration (MIC,
μM) was measured and compound with controls; the MIC
values of the compounds screened are presented in Table 1.
The antifungal screening data showed moderate activity
of the test compounds, among the screened 10b, 10f, and
10g in which isoxazole moiety bearing p-fluoro phenyl and
p-chloro phenyl nucleus, 3-hydroxy, and 4-hydroxy phenyl
nucleus on nitrogen in thiazole moiety, respectively,
showed high activity against all the microorganisms
employed. The activity of these three compounds is almost
equal to standard. It is also interesting to note that the
compounds 10b, 10f, and 10g showed activity towards C.
albicans at the concentration of 3.75 μM, which is less
than the concentration of the standard Amphotericin B.
The remaining compounds in which isoxazole moiety
bearing p-chloro phenyl and phenyl nucleus, 4-NO2, 2-
methyl, and 4-methyl nucleus in thiazole moiety showed
moderate to good antifungal activity (Table 1).
compounds screened are presented in Table 1.
EXPERIMENTAL
Commercial grade reagents were used as supplied.
Solvents except analytical reagent grade were dried and
purified according to literature when necessary. Reaction
progress and purity of the compounds were checked by
thin-layer chromatography (TLC) on pre-coated silica
gel F254 plates from Merck and compounds visualized
either by exposure to UV light or dipping in 1%
aqueous potassium permanganate solution. Silica gel
chromatographic columns (60–120 mesh) were used for
separations. Optical rotations were measured on a Perkin-
Elmer 141 polarimeter by using a 2-mL cell with a path
length of 1 dm with CHCl3 or CDCl3 as solvent. All
melting points are uncorrected and measured using
Fisher–Johns apparatus. IR spectra were recorded as KBr
disks on a Perkin-Elmer FT IR spectrometer. The
1HNMR and 13C NMR spectra were recorded on a Varian
Gemini spectrometer (300 MHz for 1H and 75 MHz
for13C). Chemical shifts are reported as δ ppm against
TMS as internal reference and coupling constants (J) are
reported in Hz units. Mass spectra were recorded on a
VG micro mass 7070H spectrometer. Elemental analyses
(C, H, N) determined by a Perkin-Elmer 240 CHN
elemental analyzer were within 0.4% of theoretical.
Nematicidal activity.
The compounds synthesized
10a–g in this study were also screened for their
nematicidal activity against Dietylenchus myceliophagus
and Caenorhabditis elegans by aqueous in vitro
screening technique [58] at various concentrations. The
nematicidal activity of each test compound was compared
with the standard drug Levamisole. The results have been
expressed in terms of LD50, i.e. median lethal dose at
which 50% nematodes became immobile (dead). The
screened data reveal that, compounds 10e and 10f in
which isoxazole moiety bearing p-fluoro phenyl and
4-methyl and 3-hydroxy phenyl nucleus on nitrogen in
thiazole moiety are the most effective against D.
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-phenylthiazolidin-4-
one (9a).
A mixture of compound 8a (0.01 mol),
p-fluoro benzaldehyde (0.02 mol), and sodium acetate
(0.01 mol) in anhydrous glacial acetic acid (20 mL)
was refluxed for 3 h. The reaction mixture was
concentrated and then poured into ice cold water; the
myceliophagus and C. elegans with LD
190 and
50
220 × 10À6 respectively; the other test compounds
Table 1
Antibacterial and nematicidal activity of 10 a–g.
Antifungal activity
Minimum inhibitory concentration (MIC, μg/mL)
Nematicidal activity
D. myceliophagus
LD 50 values
760
C. elegans
Trichophyton
rubrum
Trichophyton
mentagrophytes
Compound
C. albicans
A. fumigatus
10a
10b
10c
10d
10e
10f
10g
30.0
3.75
15.0
7.50
15.0
3.75
3.75
7.50
—
60.0
3.75
30.0
30.0
15.0
3.75
3.75
3.75
—
30.0
3.75
30.0
—
7.50
3.75
3.75
3.75
—
60.0
3.75
7.50
15.0
7.50
3.75
3.75
3.75
—
790
850
560
600
190
270
950
—
770
360
550
240
220
870
—
Amphotericin B
Levamisole
160
180
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis
solid thus separated, was filtered, washed with water,
and crystallized from glacial acetic acid. To afford pure
9a (83% yield) as yellow solid 225–228°C; IR (KBr) ν
3438, 3228, 2982, 2972, 2940, 2831, 1712, 1610,
1532, 1516, 1418, 1218, 683 cmÀ1 1HNMR (300 MHz,
DMSO-d6): δ 8.04 (s,1H,Ar―H), 7.80 (s, 1H, CH═C),
7.51 (d, J = 9.2 Hz, 2H, Ar―H), 7.42 (d, J = 8.9 Hz,
2H,Ar―H), 7.32–7.12 (5H, m, Ar –H), 6.91–6.87 (m,
5H, Ar―H + CH-S), 5.74 (d, J = 3.6 Hz,1H, C1H),
4.60 (t, J = 3.9 Hz,1H, C2H), 4.50 (s, 2H, OCH2),
3.96–3.93 (m, 1H,C4H), 3.30 (dd, J = 9.1,4.2 Hz, 1H,
C3H), 1.53 (s, 3H,CH3), 1.31 (m, 3H,CH3); 13C
NMR (75 MHz, DMSO-d6): δ 171.6, 144.2, 141.2,
138.6, 134.8, 134.2, 128.9, 128.2, 127.4,124.6, 122.2,
119.6, 119.2, 104.8, 81.2, 78.5, 74.4, 66.9,
52.0,26.5; MS: m/z (M+ + Na) 617.10. Anal. Calcd for
C32H29ClN4O5S: C, 62.28; H, 4.74; N, 9.08. Found: C,
61.53; H, 4.65; N, 9.03.The other compounds 9b–g
were also prepared by the similar procedure.
78.2, 74.8, 66.9, 52.4, 26.8; MS: m/z (M+ + Na) 692.10.
Anal. Calcd for C31H29ClFN5O7S: C, 55.56; H, 4.36; N,
10.30. Found: C, 55.26; H, 4.29; N, 10.10.
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-o-tolylthiazolidin-4-
one (9d). This compound was obtained as brown solid.
mp 201–203°C;IR (KBr) ν 3432, 3236, 2982, 2972,
2830, 1710, 1705,1610, 1548, 1514, 1418, 1260,
1
865 cmÀ1; HNMR (300 MHz, DMSO-d6): δ 8.23 (d,
J = 8.7 Hz, 2H, Ar―H), 8.04 (s,1H,Ar―H), 7.84 (s,
1H, CH═C), 7.54 (d, J = 9.2 Hz, 2H, Ar―H), 7.45–6.82
(m, 4H, Ar―H), 6.91–6.87 (m, 5H, Ar―H + CH-S),
5.74 (d, J = 3.6 Hz,1H, C1H), 4.62 (t, J = 3.9 Hz,1H,
C2H), 4.54 (s, 2H, OCH2), 3.96–3.91 (m, 1H,C4H),
3.26 (dd, J = 9.1,4.2 Hz, 1H, C3H), 2.1 (s, 3H,CH3)
1.53 (s, 3H,CH3), 1.36 (m, 3H,CH3); 13C NMR
(75 MHz, DMSO-d6):
δ
170.6, 144.6, 138.7,
134.8,134.3, 130.6, 129.4, 128.6, 125.8,125.6,122.6,
119.8, 111.6, 104.8, 81.7, 78.6, 74.7, 66.5, 52.4,
26.6,16.5; MS: m/z (M+ + H) 636.10. Anal. Calcd for
C32H30ClFN4O5S: C, 61.06; H, 4.66; N, 8.63. Found:
C, 60.86; H, 4.59; N, 8.61.
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-p-tolylthiazolidin-4-
one (9e). This compound was obtained as brown solid.
(Z)-3-(4-chlorophenyl)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorop
henyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydro
furo[2,3-d][1,3]dioxol-5-yl)-5-(4-fluorobenzylidene)thiazolidin-
4-one (9b). The compound was obtained as dark yellow
solid: mp 232–235°C; IR (KBr) ν 3432, 3226, 2981,
2969, 2822, 1714, 1610, 1535, 1510, 1409, 1216,
1
686 cmÀ1; HNMR (300 MHz, DMSO-d6): δ 8.06 (s,1H,
Ar―H), 7.82 (s, 1H, CH═C), 7.52 (d, J = 9.2 Hz, 4H,
Ar―H), 7.43 (d, J = 8.9 Hz, 4H,Ar―H), 6.91–6.87 (m,
5H, Ar―H + CH-S), 5.72 (d, J = 3.6 Hz,1H, C1H), 4.60
(t, J = 3.9 Hz,1H, C2H), 4.51 (s, 2H, OCH2), 3.96–3.91
(m, 1H,C4H,), 3.31 (dd, J = 9.1,4.2 Hz, 1H, C3H), 1.55
(s, 3H,CH3), 1.32 (m, 3H,CH3); 13C NMR (75 MHz,
mp 231–235°C; IR (KBr) ν 3428, 3230, 2986, 2976,
2832, 1708, 1698,1608, 1538, 1514, 1416, 1261,
859 cmÀ1 1HNMR (300 MHz, CDCl3): δ 8.22 (d,
;
J = 8.7 Hz, 2H, Ar―H), 8.06 (s,1H,Ar―H), 7.84 (s,
1H, CH═C), 7.54 (d, J = 9.2 Hz, 2H, Ar―H), 7.39 (d,
J = 8.33 Hz, 2H, Ar―H), 7.15 (d, J = 8.3 Hz, 2H,
Ar―H), 6.91–6.87 (m, 5H, Ar―H + CH―S), 5.76 (d,
J = 3.6 Hz,1H, C1H), 4.66 (t, J = 3.9 Hz,1H, C2H),
4.54 (s, 2H, OCH2), 3.96–3.91 (m, 1H,C4H), 3.26 (dd,
J = 9.1,4.2 Hz, 1H, C3H), 2.3 (s, 3H,CH3) 1.53 (s, 3H,
CH3), 1.36 (m, 3H,CH3); 13C NMR (75 MHz, CDCl3):
δ 172.6, 143.2, 137.4, 133.6,132.3, 131.2, 128.4,
127.9, 124.8,122.9, 119.2, 111.2, 103.8, 81.2, 78.1,
74.1, 65.9, 51.4, 26.1,16.1; MS: m/z (M+ + H) 649.10.
Anal. Calcd for C33H30ClFN4O5S: C, 61.06; H, 4.66;
N, 8.63. Found: C, 60.82; H, 4.45; N, 8.43.
DMSO-d6):
δ
170.6, 138.4, 134.8, 133.2,130.8,
129.4,128.6, 124.6, 122.2, 119.4, 111.2, 104.9, 81.5,
74.5, 66.3, 52.6, 34.6, 26.5; MS: m/z (M+ + H) 669.10.
Anal. Calcd for C32H27Cl2FN4O5S: C, 57.40; H, 4.06; N,
8.37. Found: C, 57.21; H, 4.01; N, 8.03.
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-(4-nitrophenyl)thiazo
lidin-4-one (9c). The compound was obtained as brown
solid: mp 216–218°C; IR (KBr) ν 3432, 3226, 2982,
2971, 2830, 1710, 1608, 1536, 1512, 1414,1374,
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-(3-hydroxyphenyl)
thiazolidin-4-one (9f). This compound was obtained as
1
1216, 865, 632 cmÀ1; HNMR (300 MHz, DMSO-d6): δ
8.26 (d, J = 8.7 Hz, 2H), 8.04 (s,1H,Ar―H), 7.84
(s, 1H, CH═C), 7.51 (d, J = 9.2 Hz, 2H, Ar―H), 7.42
(d, J = 8.5 Hz, 2H,Ar―H), 6.91–6.87 (m, 5H,
Ar―H + CH-S), 6.82 (d, J = 9.8 Hz, 2H, Ar―H), 5.71
(d, J = 3.6 Hz,1H, C1H), 4.62 (t, J = 3.9 Hz,1H, C2H),
4.53 (s, 2H, OCH2), 3.96–3.91 (m, 1H,C4H), 3.76 (s,
2H, CH2), 3.28 (dd, J = 9.1,4.2 Hz, 1H, C3H), 1.52 (s,
3H,CH3), 1.34 (m, 3H,CH3); 13C NMR (75 MHz,
CDCl3): δ 170.6, 147.5, 144.4, 143.2,138.4, 134.8,130.6,
131.2,128.6, 124.6, 122.4, 119.8, 111.8, 104.9, 81.5,
gray solid. mp 218–221°C; IR (KBr) ν 3533, 3424,
3230, 2982, 2970, 2831, 1710, 1614, 1537,1514, 1416,
1
1260, 864 cmÀ1; HNMR (300 MHz, DMSO – d6): δ
8.24 (d, J = 8.7 Hz, 2H, Ar―H), 8.03 (s,1H,Ar―H),
7.80 (s, 1H, CH═C), 7.56 (d, J = 9.2 Hz, 2H, Ar―H),
7.14–6.70 (m, 4H,Ar―H), 6.91–6.87 (m, 5H,
Ar―H + CH―S), 5.76 (d, J = 3.6 Hz,1H, C1H), 5.40 (s,
1H, OH), 4.66 (t, J = 3.9 Hz,1H, C2H), 4.54 (s, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Srinivas, M. Sunitha, P. Karthik, G. Nikitha, K. Raju, B. Ravinder, S. Anusha,
T. Rajasri, D. Swapna, D. Swaroopa, K. Srinivas, and K. Vasumathi Reddy
Vol 000
OCH2), 3.93–3.96 (m, 1H,C4H), 3.26 (dd, J = 9.1,4.2 Hz,
1H, C3H), 1.53 (s, 3H,CH3), 1.38 (m, 3H,CH3); 13C NMR
(75 MHz, DMSO – d6): δ 171.6, 158.3, 144.2, 143.2,
138.2, 134.6, 134.4, 130.6, 128.6,124.6, 122.2, 120.1,
119.4, 114.6, 111.8, 107.6,106.8, 81.8, 78.6, 74.8, 64.9,
54.9, 41.1; MS: m/z (M+ + Na) 673.20. Anal. Calcd for
C32H28ClFN4O6S: C, 59.03; H, 4.33; N, 8.60. Found: C,
58.82; H, 4.15; N, 8.49.
C32H29ClFN5O5S: C, 59.12; H, 4.50; N, 10.77. Found:
C, 58.83; H, 4.35; N, 10.43.The other compounds 10b–g
were also prepared by the similar procedure.
6-(4-chlorophenyl)-5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-
1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro
[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-3,3a,5,6-tetrahydro
isoxazolo[3,4-d]thiazole (10b).
The compound was
obtained as dark yellow solid mp 242–245°C; IR (KBr) ν
3482, 3233, 2980, 2972, 2942, 2821, 1714, 1600, 1572,
1518, 1416, 1212, 681 cmÀ1 1HNMR (300 MHz,
DMSO-d6): δ 8.04 (s,1H,Ar―H), 7.53 (d, J = 9.2 Hz,
2H, Ar―H), 7.42 (s, 1H, CH―N), 7.30 (d, J = 8.9 Hz,
2H,Ar―H), 7.22–7.12 (4H, m, Ar –H), 6.91–6.87 (m,
4H, Ar―H), 5.78 (d, J = 3.6 Hz,1H, C1H), 5.70 (d,
J = 2.2 Hz, 1H, CH―O), 4.69 (d, J = 2.2 Hz,1H, CH―S),
4.60 (t, J = 3.9 Hz,1H, C2H), 4.50 (s, 2H, OCH2), 3.96–
3.93 (m, 1H,C4H), 3.30 (dd, J = 9.1,4.2 Hz, 1H, C3H),
1.53 (s, 3H,CH3), 1.31 (m, 3H,CH3); 13C NMR (75 MHz,
DMSO-d6): δ 171.6,164.0,161.8,144.2, 141.2, 136.2,
138.6, 134.8, 134.2,129.6,128.9,128.2, 127.4,126.1,124.6,
122.2, 119.6, 119.2,117.5,115.7, 104.8, 81.2, 78.5,71.8,
74.4, 66.9, 52.0,40.1, 26.5; MS: m/z (M+ + Na) 672.10.
Anal. Calcd for C32H28Cl2FN5O5S: C, 56.14; H, 4.12; N,
10.23. Found: C, 56.03; H, 4.05; N, 10.13.
(Z)-2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-5-(4-fluorobenzylidene)-3-(4-hydroxyphenyl)thia
zolidin-4-one (9g). This compound was as dark yellow
solid. mp 283–285°C;IR (KBr) ν 3539, 3421, 3230,
2985, 2978, 2831, 1710, 1612, 1543,1516, 1412, 1252,
861 cmÀ1 1HNMR (300 MHz, CDCl3): δ 8.22 (d,
;
J = 8.7 Hz, 2H, Ar―H), 8.06 (s,1H,Ar―H), 7.83 (s,
1H, CH═C), 7.54 (d, J = 9.2 Hz, 2H, Ar―H),
7.10–6.70 (m, 4H,Ar―H), 6.91–6.89 (m, 5H,
Ar―H + CH―S), 5.76 (d, J = 3.6 Hz,1H, C1H), 5.28
(s, 1H, OH), 4.65 (t, J = 3.9 Hz,1H, C2H), 4.52(s, 2H,
OCH2),
3.91–3.94
(m,
1H,C4H),
3.34
(dd,
J = 9.1,4.2 Hz, 1H, C3H), 1.52 (s, 3H,CH3), 1.36 (m,
3H,CH3); 13C NMR (75 MHz, CDCl3): δ 171.2, 157.8,
143.8, 143.2, 133.9, 133.4, 130.2, 127.6, 121.9, 120.5,
1198.8, 114.2, 111.2, 106.8, 81.4, 78.2, 73.8, 62.9, 54.2,
40.9, 34.9; MS: m/z (M+ + H) 651.20. Anal. Calcd for
C32H28ClFN4O6S: C, 59.03; H, 4.32; N, 8.59. Found: C,
58.72; H, 4.29; N, 8.42.
5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-3-(4-fluorophenyl)-6-(4-nitrophenyl)-3,3a,5,6-tetrahydroiso
xazolo[3,4-d]thiazole (10c). The compound was obtained as
red solid. mp 251–255°C; IR (KBr) ν 3484, 3237, 2985,
2974, 2944, 2825, 1714, 1600, 1572,1535, 1518, 1416,
1215, 681 cmÀ1 1HNMR (300 MHz, DMSO-d6): δ 8.04
(s,1H,Ar―H), 7.56 (d, J = 9.2 Hz, 2H, Ar―H), 7.44 (s,
1H, CH―N), 7.30 (d, J = 8.9 Hz, 2H,Ar―H), 7.22–
7.12 (4H, m, Ar –H), 6.91–6.87 (m, 4H, Ar―H), 5.78
(d, J = 3.6 Hz,1H, C1H), 5.72 (d, J = 2.2 Hz, 1H,
CH―O), 4.70 (d, J = 2.2 Hz,1H, CH―S), 4.60 (t,
J = 3.9 Hz,1H, C2H), 4.50 (s, 2H, OCH2), 3.96–3.93 (m,
1H,C4H), 3.30 (dd, J = 9.1,4.2 Hz, 1H, C3H), 1.53 (s,
3H,CH3), 1.31 (m, 3H,CH3); 13C NMR (75 MHz,
DMSO-d6): δ 171.4,163.0,161.8,143.2, 140.2, 135.2,
134.6,134.2,129.6,128.6,128.2, 127.6,126.1,124.4, 122.2,
119.5, 119.0,117.2,115.3, 104.5, 81.7, 78.2,71.7, 74.1,
66.9, 52.0,40.1, 26.5; MS: m/z (M+ + Na) 695.10. Anal.
Calcd for C32H28ClFN6O7S: C, 55.29; H, 4.06; N, 12.09.
Found: C, 55.03; H, 3.95; N, 11.83.
5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-3-(4-fluorophenyl)-6-phenyl-3,3a,5,6-tetrahydroisoxazolo
[3,4-d]thiazole (10a).
A mixture of compound 9a
(0.01 mol), hydroxyl amine hydrochloride (0.02 mol)
and sodium acetate (0.01 mol) in anhydrous glacial
acetic acid (20 mL), was refluxed for 8 h.The reaction
mixture was concentrated and then poured into ice cold
water, the solid thus separated, was filtered, washed
with ice water, and crystallized from ethanol to afford
pure 10a (87% yield) as brown solid: mp 255–258°C;
IR (KBr) ν 3478, 3238, 2982, 2972, 2940, 2831, 1712,
1600, 1570, 1516, 1418, 1218, 683 cmÀ1 1HNMR
(300 MHz, DMSO-d6): δ 8.04 (s,1H,Ar―H), 7.51 (d,
J = 9.2 Hz, 2H, Ar―H), 7.45 (s, 1H, CH―N), 7.40 (d,
J = 8.9 Hz, 2H,Ar―H), 7.32–7.12 (5H, m, Ar –H),
6.91–6.87 (m, 4H, Ar―H), 5.78 (d, J = 3.6 Hz,1H,
C1H), 5.70 (d, J = 2.2 Hz, 1H, CH―O), 4.69 (d,
J = 2.2 Hz,1H, CH―S), 4.60 (t, J = 3.9 Hz,1H, C2H),
4.50 (s, 2H, OCH2), 3.96–3.93 (m, 1H,C4H), 3.30 (dd,
J = 9.1,4.2 Hz, 1H, C3H), 1.53 (s, 3H,CH3), 1.31 (m, 3H,
5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl)-3-(4-fluorophenyl)-6-o-tolyl-3,3a,5,6-tetrahydroisoxazolo
[3,4-d]thiazole (10d).
The compound was obtained as
yellow solid. mp 189–193°C;IR (KBr) ν 3428, 3231,
CH3); 13C NMR (75 MHz, DMSO-d6):
δ
2980, 2970, 2820, 1710, 1705,1600, 1548, 1510, 1418,
1250, 862 cmÀ1 1HNMR (300 MHz, DMSO-d6): δ
;
171.6,164.0,161.8, 144.2, 141.2, 136.2, 138.6, 134.8,
134.2, 128.9, 128.2, 127.4,124.6, 122.2, 119.6,
119.2,115.7, 104.8, 81.2, 78.5,71.8, 74.4, 66.9, 52.0,40.1,
26.5; MS: m/z (M+ + Na) 672.10. Anal. Calcd for
8.23 (d, J = 8.7 Hz, 2H, Ar―H), 8.04 (s,1H,Ar―H),
7.54 (d, J = 9.2 Hz, 2H, Ar―H), 7.45 (s, 1H, CH―N),
7.25–6.82 (m, 4H, Ar―H), 6.91–6.87 (m, 4H, Ar―H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis
5.72 (d, J = 2.2 Hz, 1H, CH―O), 5.68 (d, J = 2.2 Hz, 1H,
S―CH), 5.64 (d, J = 3.6 Hz,1H, C1H), 4.62 (t,
J = 3.9 Hz,1H, C2H), 4.54 (s, 2H, OCH2), 3.96–3.91
(m, 1H,C4H), 3.26 (dd, J = 9.1,4.2 Hz, 1H, C3H), 2.1
(s, 3H,CH3) 1.53 (s, 3H,CH3), 1.36 (m, 3H,CH3); 13C
NMR (75 MHz, DMSO-d6): δ 170.6, 144.6, 138.7,
134.8,134.3, 130.6, 129.4, 128.6, 125.8,125.6,122.6,
119.8, 111.6, 104.8, 81.7, 78.6, 74.7, 66.5, 52.4, 26.6,
21.3; MS: m/z (M+ + H) 664.10. Anal. Calcd for
C33H31ClFN5O5S: C, 59.68; H, 4.70; N, 10.54. Found:
C, 59.26; H, 4.59; N, 10.31.
4-(5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-3-(4-fluorophenyl)-3,3a-dihydrothiazolo[4,5-c]
isoxazol-6(5H)-yl)phenol (10g).
This compound was as
brown solid. mp 273–275°C;IR (KBr) ν 3539, 3421, 3230,
2985, 2978, 2831, 1710, 1600, 1516, 1412, 1252,
861 cmÀ1 1HNMR (300 MHz, DMSO-d6): δ 8.23 (d,
;
J = 8.7 Hz, 2H, Ar―H), 8.04 (s,1H,Ar―H), 7.54 (d,
J = 9.2 Hz, 2H, Ar―H), 7.40 (s, 1H, CH―N), 7.10–6.70
(m, 4H,Ar―H), 6.91–6.89 (m, 4H, Ar―H), 5.76 (d,
J = 3.6 Hz,1H, C1H), 5.70 (d, J = 2.2 Hz, 1H, CH―O),
5.67 (d, J = 2.2 Hz, 1H, S―CH) 5.28 (s, 1H, OH), 4.65 (t,
J = 3.9 Hz,1H, C2H), 4.52(s, 2H, OCH2), 3.91–3.94 (m,
1H,C4H), 3.34 (dd, J = 9.1,4.2 Hz, 1H, C3H), 1.52 (s, 3H,
CH3), 1.36 (m, 3H,CH3); 13C NMR (75 MHz, CDCl3): δ
171.2, 157.8, 143.8, 143.2, 133.9, 133.4, 130.2, 127.6,
121.9, 120.5, 1198.8, 114.2, 111.2, 106.8, 81.4, 78.2, 73.8,
62.9, 54.2, 40.9, 34.9; MS: m/z (M+ + Na) 688.20. Anal.
Calcd for C32H29ClFN5O6S: C, 57.70; H, 4.39; N, 10.51.
Found: C, 57.42; H, 4.45; N, 10.49.
5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-
5-yl)-3-(4-fluorophenyl)-6-p-tolyl-3,3a,5,6-tetrahydroisoxazo
lo[3,4-d]thiazole (10e). The compound was obtained as
brown solid. mp 221–225°C; IR (KBr) ν 3428, 3230,
2986, 2976, 2832, 1708, 1698,1600,1570, 1514, 1416,
1261, 859 cmÀ1 1HNMR (300 MHz, DMSO-d6): δ
;
8.22 (d, J = 8.7 Hz, 2H, Ar―H), 8.06 (s,1H,Ar―H),
7.54 (d, J = 9.2 Hz, 2H, Ar―H), 7.42 (s, 1H, CH―N)
7.39 (d, J = 8.33 Hz, 2H, Ar―H), 7.15 (d, J = 8.3 Hz,
2H, Ar―H), 6.91–6.87 (m, 4H, Ar―H), 5.76 (d,
J = 3.6 Hz,1H, C1H), 5.70 (d, J = 2.2 Hz, 1H,
CH―O), 5.62 (d, J = 2.2 Hz, 1H, S―CH), 4.66 (t,
J = 3.9 Hz,1H, C2H), 4.54 (s, 2H, OCH2), 3.96–3.91
(m, 1H,C4H), 3.26 (dd, J = 9.1,4.2 Hz, 1H, C3H), 2.3
(s, 3H,CH3) 1.53 (s, 3H,CH3), 1.36 (m, 3H,CH3); 13C
NMR (75 MHz, DMSO – d6): δ 172.6, 143.2, 137.4,
133.6,132.3, 131.2, 128.4, 127.9, 124.8,122.9, 119.2,
111.2, 103.8, 81.2, 78.1, 74.1, 65.9, 51.4, 26.1,16.1;
CONCLUSION
In conclusion, a series of a new class of hybrid
heterocyclics 10a–g have been synthesized. The antifungal
activity of these compounds was evaluated against various
fungi. Among synthesized compounds 10b, 10f, and 10g
showed good activity and emerged as potential molecules
for further development. The compounds also were also
evaluated for their nematicidal activity. 10e and 10f
showed an appreciable nematicidal activity.
MS: m/z (M+
+ Na) 686.10. Anal. Calcd for
C33H31ClFN5O5S: C, 59.68; H, 4.70; N, 10.54. Found:
C, 59.52; H, 4.55; N, 10.43.
3-(5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-3-(4-fluorophenyl)-3,3a-dihydrothiazolo[4,5-c]iso
xazol-6(5H)-yl)phenol (10f). The compound was obtained
Acknowledgments. The authors are thankful to CSIR-New Delhi
for the financial support (Project funding No: 02 (247)15/EMR-
II), Director, CSIR-IICT, Hyderabad, India, for NMR and MS
spectral analysis and Principal, Vaagdevi Degree and PG College
Hanamkonda for his constant encouragement.
as gray solid. mp 228–231°C; IR (KBr) ν 3533, 3424,
3230, 2982, 2970, 2831, 1710, 1600,1514, 1416, 1260,
1
864 cmÀ1; HNMR (300 MHz, DMSO – d6): δ 8.22 (d,
J = 8.7 Hz, 2H, Ar―H), 8.01 (s,1H,Ar―H), 7.54 (d,
J = 9.2 Hz, 2H, Ar―H), 7.42 (s, 1H, CH―N), 7.14–
6.90 (m, 4H,Ar―H), 6.88–6.86 (m, 4H, Ar―H), 5.62
(d, J = 2.2 Hz, 1H, S―CH), 5.74 (d, J = 3.6 Hz,1H,
C1H), 5.70 (d, J = 2.2 Hz, 1H, CH―O), 5.39 (s, 1H,
OH), 4.64 (t, J = 3.9 Hz,1H, C2H), 4.52 (s, 2H, OCH2),
3.95–3.93 (m, 1H,C4H), 3.24 (dd, J = 9.1,4.2 Hz, 1H,
C3H), 1.51 (s, 3H,CH3), 1.34 (m, 3H,CH3); 13C NMR
(75 MHz, DMSO – d6): δ 171.6, 158.3, 145.8,144.2,
143.2, 134.6, 134.4, 130.6, 128.6,122.2, 120.1, 119.4,
114.6, 111.8, 107.6,106,98.2, 81.8, 78.6, 74.8, 64.9,
54.9, 41.1; MS: m/z (M+ + H) 666.20. Anal. Calcd for
C32H29ClFN5O6S: C, 57.70; H, 4.39; N, 10.51. Found:
C, 57.32; H, 4.15; N, 10.39.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet