Synthesis of some novel methylene-bis-pyrimidinyl-spiro-4-thiazolidinones as biologically potent agents

Article abstract of DOI:10.1002/jhet.5570450428

(Chemical Equation Presented) A series of novel methylene-bis-pyrimidinyl- spiro-4-thiazolidinones 6a-h have been synthesized by cyclocondensation of thioglycolic acid with methylene-bis-(N-cyclohexylidene-N-pyrimidine) 5a-h, which in turn have been prepa

Full text of DOI:10.1002/jhet.5570450428

Jul-Aug 2008
1121
Synthesis of Some Novel Methylene-bis-pyrimidinyl-spiro-4-
thiazolidinones as Biologically Potent Agents
A. Srinivas, A. Nagaraj and Ch. Sanjeeva Reddy*
Department of Chemistry, Kakatiya University, Warangal 506 009, India.
E-mail: chsrkuc@yahoo.co.in
Received October 31, 2007
R
R
R
OH
OH
N
O
H2N
N
O
R
N
N
NH2
HO
HO
4
3
R
S
OH
R
N
N
O
R
N
N
OH
N
N
N
N
N
N
N
S
R
N
O
HO
HO
6
5
A series of novel methylene-bis-pyrimidinyl-spiro-4-thiazolidinones 6a-h have been synthesized by
cyclocondensation of thioglycolic acid with methylene-bis-(N-cyclohexylidene-N-pyrimidine) 5a-h, which
in turn have been prepared by the reaction of cyclohexanone with methylene-bis-2-aminopyrimidines 4a-h,
which are prepared by the reaction of guanidine hydrochloride with methylene-bis-chalcones 3a-h. The
compounds 3a-h have been synthesized by the reaction of 5-(3-formyl-4-hydroxybenzyl)-2-hydroxy-
benzaldehyde 2 with various acetophenones in presence of KOH. The compound 2 is prepared by the
reported method. The structures of the compounds synthesized have been confirmed by their elemental
analysis and spectral data. Their antibacterial and antifungal activities have also been evaluated.
J. Heterocyclic Chem., 45, 1121 (2008).
INTRODUCTION
complications like cataracts, nephropathy and neuropathy
[17], and selective anti-platelet activating factor [18].
Inspite of wide applications, it has been observed that
there is scant information on the synthesis of
thiazolidinones possessing heteryl substituted pyrimidinyl
moiety in the literature.
In the course of work on new pharmacologically active
thiazolidinones extensive efforts have been made to find
more potent agents. The utility of 4-thiazolidinone/
thiazole as clinical agents and industrial intermediates is
well established [1]. The 4-thiazolidinone/thiazole
nucleus also frequently appears in the structure of various
natural products and biologically active compounds,
notably thiamine, penicillin, antibiotics such as
micrococcin [2a], compounds possessing cardiac and
glycemic benefit such as troglitazone [2b] and many
metabolic products of fungi and primitive marine animals,
including 2-(aminoalkyl)-thiazole-4-carboxylic acids [2c].
Recently more attention has been directed towards the
On the other hand the pyrimidines have a unique place
and have contributed significantly to biological and
medicinal fields [19] such as antitubercular [20], and
calcium channel blockers [21], and also many pyrimidines
[22] have displayed diverse pharmaceutical activities
depending upon the geometry and type of substituents
attached to the ring [23]. 3-Azido-3-deoxythymidine
(AZT) [24] a pyrimidine derivative has been found to be a
potent antiviral agent against HIV type 1 in vitro, and has
been found to decrease mortality and opportunistic
infections in patients with AIDS. Inspired by the
biological profile of thiazolidinones and pyrimidine
derivatives and their increasing importance in
pharmaceutical and biological fields, and in continuation
of our work on the synthesis of biologically active
heterocycles [25] considering the scope to introduce
pyrimidinyl moiety into thiazolidinones, it was thought
synthesis
of
thiazolidinone
bearing
heteryl
pharmacophores [3] as some of the deriva- tives have
displayed significant pharmacological [4], and biological
activities [5] including sedative [6], antiinflam-matory
[7], antibacterial [8], antifungal [9], antitubercu- lar [10],
analgesic and hypothermic [11], local [12a] and spinal
[12b] anesthetic, CNS stimulant [13], anti-HIV [14] and
nematicidal [15]. Further, thiazolidinones have also been
used for the treatment of cardiac diseases [16], diabetic

1122
A. Srinivas, A. Nagaraj and Ch. Sanjeeva Reddy
Vol 45
Scheme 1
R
OH
CHO
O
O
OH
HO
OH
O
R
R
Me
Trioxane
KOH/EtOH
H2SO4/AcOH
CHO
CHO
HO
3
1
2
H2NCNHNH2
NaOH/H2O
R
R
N
N
OH
N
N
R
N
R
N
OH
O
N
H2N
N
N
HO
N
AcOH/PhMe
NH2
5
HO
4
HSCH2COOH
Anhy.ZnCl2
R
S
3/4/5/6
3/4/5/6
R
R
OH
N
N
O
C6H5
e
f
g
h
4-MeO-C6H4
2-OH-C6H4
2-Furyl
a
b
c
d
4-Br-C6H4
4-NO2-C6H4
4-Cl-C6H4
N
N
N
N
S
R
2-Thienyl
O
HO
6
worthwhile to undertake the synthesis of the title
compounds with the view to obtain certain new chemical
entities with both active pharmacophores in a single
molecular framework for the intensified biological
activities.
guanidine hydrochloride in the presence of aqueous
NaOH to get the corresponding methylene-bis-2-amino-
pyrimidines 4 in excellent yields [25g]. These compounds
have low solubility in the most common solvents, hence
were purified in small quantities by crystallizing the solid
products in appropriate amounts of ethyl alcohol/benzene.
The methylene-bis-2-aminnopyrimidine 4 was reacted
with cyclohexanone in toluene in the presence of acetic
acid to give the corresponding methylene-bis-(N-cyclo-
hexylidene-N-pyrimidine) 5 in good yields. The one-pot
synthesis of novel methylene-bis-pyrimidinyl-spiro-4-thi-
azolidinones 6a-h was carried out by the cyclocondensa-
tion reaction between compound 5 and thioglycolic acid
in N,N-dimethylformamide in the presence of anhy. ZnCl2
under conventional heating. The structures of all the new
In this article, we wish to report the synthesis of novel
methylene-bis-pyrimidinyl-spiro-4-thiazolidinones
6 in
good yields, from methylene-bis-(N-cyclohexylidene-N-
pyrimidine) 5 and thioglycolic acid (Scheme 1). The
antibacterial and antifungal activities of the compounds
6a-h have also been evaluated.
RESULTS AND DISCUSSION
The title methylene-bis-pyrimidinyl-spiro-4-thiazolidi-
nones 6 were synthesized from the methylene-bis-(N-
cyclohexylidene-N-pyrimidine) 5. For the synthesis of the
target compounds, the 5-(3-formyl-4-hydroxybenzyl)-2-
hydroxybenzaldehyde 2 was prepared by the reaction of
salicylaldehyde 1 with trioxane in the presence of a
mixture of acetic acid and conc. sulfuric acid [26],
subsequent condensation with acetophenones in the
presence of 60% aqueous KOH at room temperature [25e]
yields methylene-bis-chalcones 3. The reaction times,
and the yields, vary depending on the corresponding
reagents. The crude products, contaminated by some
starting materials, were purified by extracting with ether.
1
compounds were confirmed by IR, H NMR, 13C NMR,
MS and elemental analyses and further screened for their
antibacterial and antifungal activities.
Antibacterial Activity. The compounds 6a-h were
screened for their antibacterial activity against human
pathogenic bacteria Escherichia coli, Klebseilla
pneumoniae, Shigella dysentriae and Shigella flexnei.
The zone of inhibition in mm at concentration 100 μg was
determined using the cup plate method [27]. Standard
antibacterial agents such as streptomycin and neomycin,
were also screened under similar conditions for the
comparison and the results are given in Table 1.
The methylene-bis-chalcones
3 were reacted with

Jul-Aug 2008
Synthesis of Methylene-bis-pyrimidinyl-spiro-4-thiazolidinones
1123
the compounds was checked using precoated TLC plates. IR
spectra were obtained on a Perkin-Elmer BX serried FTIR 5000
spectrophotometer, using KBr pellet. 1H NMR, 13C NMR spectra
were obtained on a Varian Gemini spectrometer at 300 MHz,
The antibacterial screening of the compounds 6a-h
showed that compounds 6b, 6d and 6f were highly active
against K. pneumoniae and S. dysentriae. The compounds
6d, 6e and 6g showed significant activity against S.
flexnei. Compound 6d is highly active against all the test
organisms employed. The other compounds showed either
moderate or less activity against these organisms. In case
of E. coli all the compounds have displayed significant
activity.
and 100 MHz , the chemical shifts ware reported as
ppm
down field using TMS as an internal standard and J values are
quoted in Hz. Mass spectra were recorded on a VG-Micromass
7070H spectrometer operat- ing at 70 eV. Satisfactory elemental
analyses was obtained using a Perkin-Elmer CHN analyzer. All
solvents and chemicals were purchased from Sigma Aldrich
chemical company and used without further purification.
Table 1
Antimicrobial activity of compounds 6a-h.
Antibacterial activity
(zone of inhibition in mm at 100 μg)
Antifungal activity
(zone of inhibition in mm at 500 μg)
Compd
E.coli
21
19
23
27
19
20
23
20
30
20
--
K.pneumoniae
S.dysentriae
S. flexnei
19
17
A.niger
18
22
C.albicans
A.flavus
18
15
R.oryzae
14
19
6a
6b
6c
6d
6e
6f
6g
17
20
19
26
11
21
18
17
30
20
--
17
21
24
27
20
22
23
15
30
20
--
17
16
27
20
17
24
24
22
--
19
26
25
19
19
16
30
20
25
24
18
24
19
26
--
23
21
19
22
16
20
--
19
26
16
20
24
26
--
6h
SM
NM
GF
--
32
--
32
--
30
--
32
--
SM = Streptomycin; NM = Neomycin; GF = Griseofulvin.
Note: <16mm, inactive; 17-23mm, moderately active; 23-27mm, highly active.
Synthesis of methylene-bis-chalcones (3a-h). A solution of
Antifungal Activity. The compounds 6a-h were also
2 (2.56 g, 0.01 mol) and 4-bromoacetophenone (0.02 mol) in
absolute ethyl alcohol (20 mL) was treated with 60% KOH
solution (20 mL) at 5-10 °C. The reaction mixture was stirred at
room temperature for 4 hours. It was then diluted with water (50
mL) and extracted with diethyl ether (3x20 mL). The aqueous
solution was acidified with dilute HCl. The solid obtained was
collected by filtration, washed thoroughly with water, dried and
purified by crystallization from toluene:MeOH (3:2) to give pure
screened for their antifungal activity against Aspergillus niger,
Candida albicans, Aspergillus flavus and Rhizopus oryzae at
concentration of 500 μg using cup plate method [27]. The
antifungal activity of the compounds was compared with the
standard drug griseofulvin, the zones of inhibition formed
were measured in mm and are shown in Table 1.
The antifungal screening of the compounds 6a-h showed
that compounds 6d and 6f were significantly active and 6h is
highly active against all the test organisms. Compound 6c is
highly active against A. niger, C. albicans and A. flavus,
compound 6g is also highly active against C. albicans and R.
oryzae. The other compounds showed either moderate or
less activity against these organisms.
1
3b as yellow solid (91%), mp 160-62 °C; H NMR (DMSO-d6):
10.21 (2H, s, OH), 8.18-7.82 (6H, m, ArH), 8.05 (4H, d, J = 9.0
Hz, ArH), 7.70 (2H, d, J = 16.4 Hz, ꢀ-H), 7.18 (4H, d, J = 9.0
Hz, ArH), 6.84 (2H, d, J = 16.4 Hz, ꢁ-H), 3.84 (2H, s, CH2); IR
(KBr): ꢀ 3440, 3056, 1640, 1571, 1482, 1224 cm-1; MS: m/z 616
(M+). Anal. calcd. for C31H22Br2O4: C, 60.22; H, 3.59; Br, 25.85.
Found: C, 60.12; H, 3.59; Br, 25.61. The other chalcones 3 were
1
In conclusion, we have described the synthesis of novel
prepared by the similar procedure and characterized by IR, H
NMR, MS and elemental analyses [25e].
methylene-bis-pyrimidinyl-spiro-4-thiazolidinones
good to excellent yields by the reaction of methylene-bis-
(N-cyclohexylidene-N-pyrimidine) and thioglycolic
6 in
Synthesis of methylene-bis-2-aminopyrimidines (4a-h). A
solution of 3b (0.01 mol) and guanidine hydrochloride (0.03
mol) in ethyl alcohol (20 mL) was added aq. NaOH (0.02 mol)
solution (5 mL). The reaction mixture was refluxed, TLC
(EtOAc: Pet-ether, 2:1) showed that the reaction was complete
after 6 hours. Then it was poured in cold 10% HCl (50 mL)
solution and the precipitate obtained was collected by filtration,
washed with water until free from acid and recrystallized from
toluene-ethanol (3:2) to give pure 4b as brown solid (83%), mp
5
acid. Some of these compounds exhibit excellent antibac-
terial and antifungal activities and can be evaluated as
antimicrobial agents.
EXPERIMENTAL
1
123-25 °C; H NMR (DMSO-d6): ꢁ 7.72 (4H, d, J = 8.1 Hz,
ArH), 7.69 (4H, d, J = 8.1 Hz, ArH), 6.89-7.59 (8H, m, ArH),
The melting points were determined on a Fisher-Johns
melting points apparatus and were uncorrected. The purity of

1124
A. Srinivas, A. Nagaraj and Ch. Sanjeeva Reddy
Vol 45
7.10 (2H, s, OH), 7.03 (4H, s NH2), 4.06 (2H, s, CH2); IR (KBr):
ꢀ 3392, 3047, 2587, 1627, 1471 cm-1; MS: m/z 694 (M+). Anal.
calcd. for C33H24Br2N6O2: C, 56.92; H, 3.47; N, 1207. Found: C,
56.83; H, 3.41; N, 12.01. The other methylene-bis-2-amino-
pyrimidines 4 were prepared by the similar procedure and their
structures and biological activities are also evaluated [25g].
Synthesis of methylene-bis-(N-cyclohexylidene-N-
pyrimidine) (5a-h). A mixture of compound 4b (0.01 mol),
cyclohexanone (0.02 mol) and acetic acid (0.5 mL) was refluxed
in toluene using a Dean-Stark apparatus and the water formed
was removed azeotropically. The progress of the reaction was
checked by TLC using toluene: ethyl acetate (4:1) as an eluent.
After completion of the reaction (5 hours), solvent was removed
by distillation to give solid, which was collected by filtration,
and recrystallized from absolute ethyl alcohol to give pure 5b as
= 8.7 Hz, ArH), 7.40-7.32 (6H, m, ArH), 6.72 (2H, d, J = 9.2
Hz, ArH), 4.10 (2H, s, CH2), 3.78 (4H, s, CH2), 2.10-1.50 (20H,
m, CH2); 13C NMR (DMSO-d6): ꢁ 176.2, 162.6, 158.4, 152.6,
152.0, 147.3, 144.7, 141.3, 132.6, 130.7, 128.1, 124.7, 116.7,
115.2, 109.0, 87.3, 47.3, 42.1, 36.3, 30.1, 26.4; IR (KBr): ꢀ
3340, 3015, 2985, 1670, 1610, 1510, 1475, 1415, 1318, cm-1;
MS: m/z 936 (M+). Anal. calcd. for C49H44N8O8S2: C, 62.81; H,
4.73; N, 11.96. Found: C, 62.37; H, 4.70; N, 11.82.
4-[4-(4-Chlorophenyl)-6-(5-{3-[6-(4-chlorophenyl)-2-(3-oxo-
1-thia-4-azaspiro[4.5]dec-4-yl)-4-pyrimidinyl]-4-hydroxybenz-
yl}-2-hydroxyphenyl)-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]
decan-3-one (6d). Mp 165-67°C; Yield 76%; 1H NMR (DMSO-
d6): ꢁ 10.40 (2H, s, OH), 7.84 (4H, d, J = 8.4 Hz, ArH), 7.40-
7.32 (6H, m, ArH), 7.15 (4H, d, J = 8.4 Hz, ArH), 6.72 (2H, d, J
= 9.2 Hz, ArH), 4.12 (2H, s, CH2), 3.80 (4H, s, CH2), 2.10-1.50
(20H, m, CH2); 13C NMR (DMSO-d6): ꢁ 175.4, 162.0, 157.6,
152.7, 152.0, 143.9, 140.1, 134.6, 132.9, 132.1, 129.1, 126.6,
116.3, 115.0, 112.1, 87.1, 47.4, 42.1, 36.5, 30.0, 26.1; IR (KBr):
ꢀ 3340, 3027, 2985, 1675, 1610, 1480, 1470, 1410, 746, 686
cm-1; MS: m/z 916 (M+). Anal. calcd. for C49H44Cl2N6O4S2: C,
64.25; H, 4.84; N, 9.18. Found: C, 64.16; H, 4.72; N, 9.10.
4-[4-(2-Hydroxy-5-{4-hydroxy-3-[6-(4-methoxyphenyl)-2-
(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-4-pyrimidinyl]benz-
yl}phenyl)-6-(4-methoxyphenyl)-2-pyrimidinyl]-1-thia-4-aza-
spiro[4.5]decan-3-one (6e). Mp 180-82°C; Yield 88%; 1H
NMR (DMSO-d6): ꢁ 10.40 (2H, s, OH), 7.90 (4H, d, J = 8.3 Hz,
ArH), 7.40-7.32 (6H, m, ArH), 7.00 (4H, d, J = 8.3 Hz, ArH),
6.72 (2H, d, J = 9.2 Hz, ArH), 4.12 (2H, s, CH2), 3.80 (4H, s,
CH2), 3.70 (6H, s, OCH3), 2.10-1.50 (20H, m, CH2); 13C NMR
(DMSO-d6): ꢁ 175.3, 162.3, 160.1, 157.9, 152.3, 152.0, 144.0,
139.3, 132.7, 131.7, 126.8, 116.2, 113.2, 111.7, 114.2, 87.8,
47.0, 42.0, 36.7, 30.1, 26.0; IR (KBr): ꢀ 3344, 3027, 2980, 1672,
1600, 1480, 1472, 1410, 1224, 688 cm-1; MS: m/z 906 (M+).
Anal. calcd. for C51H50N6O6S2: C, 67.53; H, 5.56; N, 9.26.
Found: C, 67.42; H, 5.50; N, 9.21.
1
brown solid (74%), mp 172-74°C; H NMR (DMSO-d6): ꢁ 10.2
(2H, s OH), 7.72 (4H, d, J = 8.1 Hz, ArH), 7.69 (4H, d, J = 8.1
Hz, ArH), 7.59-6.89 (8H, m ArH), 4.06 (2H, s, CH2), 2.50-2.40
(8H, m, CH2), 2.34-2.28 (8H, m, CH2), 1.62-1.59 (4H, m, CH2);
IR (KBr): ꢀ 3410, 3062, 1625, 1471, 584 cm-1; MS: m/z 856
(M+). Anal. calcd. for C45H40Br2N6O2: C, 63.09; H, 4.71; N, 9.81.
Found: C, 62.94; H, 4.65; N, 9.77.
General procedure for the synthesis of compounds (6a-h).
A mixture of compound 5 (0.01 mol) and thioglycolic acid (2.1
mL, 0.03 mol) in N,N-dimethylformamide (40 mL) with a pinch
of anhydrous ZnCl2, was refluxed for 6 hours. The progress of
the reaction was checked by TLC using toluene:ether (3:1) as an
eluent. The reaction mixture was cooled to room temperature
and then poured into crushed ice. It was set-aside at room
temperature overnight. The solid thus separated was filtered,
washed several times with water, dried and purified by
recrystallization from alcohol.
4-[4-(2-Hydroxy-5-{4-hydroxy-3-[2-(3-oxo-1-thia-4-azaspi-
ro[4.5]dec-4-yl)-6-phenyl-4-pyrimidinyl]benzyl}phenyl)-6-
phenyl-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]decan-3-one (6a).
1
Mp 143-45°C; Yield 83%; H NMR (DMSO-d6): ꢁ 10.40 (2H, s,
4-[4-(2-Hydroxy-5-{4-hydroxy-3-[6-(2-hydroxyphenyl)-2-
(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-4-pyrimidinyl]benzyl}-
phenyl)-6-(2-hydroxyphenyl)-2-pyrimidinyl]-1-thia-4-azaspi-
OH), 7.70-7.60 (10H, m, ArH), 7.40-7.32 (6H, m, ArH), 6.72 (2H,
d, J = 9.2 Hz, ArH), 4.10 (2H, s, CH2), 3.77 (4H, s, CH2), 2.10-
1.50 (20H, m, CH2); 13C NMR (DMSO-d6): ꢁ 175.6, 163.9, 158.6,
152.7, 152.0, 144.3, 136.4, 133.1, 131.0, 129.3, 128.7, 125.6,
111.0, 117.1, 115.9, 87.7, 47.3, 42.1, 36.7, 30.0, 26.3; IR (KBr): ꢀ
3340, 3027, 2980, 1670, 1610, 1480, 1470, 1410, 688 cm-1; MS:
m/z 846 (M+). Anal. calcd. for C49H46N6O4S2: C, 69.48; H, 5.47;
N, 9.92. Found: C, 69.36; H, 5.50; N, 9.86.
4-[4-(4-Bromophynyl)-6-(5-{3-[6-(4-bromophenyl)-2-(3-oxo-
1-thia-4-azaspiro[4.5]dec-4-yl)4-pyrimidinyl]-4-hydroxybenz-
yl}-2-hydroxyphenyl)-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]-
decan-3-one (6b). Mp 148-50°C; Yield 81%; 1H NMR (DMSO-
d6): ꢁ 10.40 (2H, s, OH), 7.70 (4H, d, J = 8.4 Hz, ArH), 7.62
(4H, d, J = 8.4 Hz, ArH), 7.40-7.32 (6H, m, ArH), 6.72 (2H, d, J
= 9.2 Hz, ArH), 4.10 (2H, s, CH2), 3.78 (4H, s, CH2), 2.10-1.50
(20H, m, CH2); 13C NMR (DMSO-d6): ꢁ 175.6, 163.2, 158.6,
152.6, 152.0, 144.3, 137.9, 133.7, 133.4, 131.2, 129.0, 124.1,
116.2, 115.6, 113.3, 87.6, 47.1, 42.1, 36.7, 30.1, 26.3; IR (KBr):
ꢀ 3340, 3020, 2995, 1676, 1595, 1480, 1470, 790, 686 cm-1; MS:
m/z 1004 (M+). Anal. calcd. for C49H46Br2N6O4S2: C, 58.57; H,
4.41; N, 8.36. Found: C, 58.46; H, 4. 39; N, 8.29.
1
ro[4.5]decan-3-one (6f). Mp 162-64°C; Yield 86%; H NMR
(DMSO-d6): ꢁ 10.40 (2H, s, OH), 7.50-6.80 (16H, m, ArH), 4.10
(2H, s, CH2), 3.78 (4H, s, CH2), 2.10-1.50 (20H, m, CH2); 13C
NMR (DMSO-d6): ꢁ 175.1, 162.4, 160.7, 156.3, 154.1, 152.0,
144.0, 132.0, 131.6, 130.1, 128.7, 122.0, 118.7, 118.1, 117.1,
116.2, 87.6, 47.9, 42.3, 36.3, 30.4, 26.2; IR (KBr): ꢀ 3541, 3015,
2985, 1670, 1600, 1472, 1415, 688 cm-1; MS: m/z 878 (M+).
Anal. calcd. for C49H46N6O6S2: C, 66.95; H, 5.27; N, 9.56.
Found: C, 66.82; H, 5.19; N, 9.43.
4-[4-(2-Furyl)-6-(5-{3-[6-(2-furyl)-2-(3-oxo-1-thia-4-azaspi-
ro[4.5]dec-4-yl)-4-pyrimidinyl]-4-hydroxybenzyl}-2-hydroxy-
phenyl)-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]decan-3-one
1
(6g). Mp 201-03°C; Yield 71%; H NMR (DMSO-d6): ꢁ 10.40
(2H, s, OH), 8.21 (2H, s, ArH), 7.40-6.30 (12H, m, ArH), 4.10
(2H, s, CH2), 3.87 (4H, s, CH2), 2.10-1.50 (20H, m, CH2); 13C
NMR (DMSO-d6): ꢁ 176.7, 175.6, 161.7, 156.7, 152.0, 150.2,
147.1, 143.7, 132.2, 131.0, 118.3, 116.7, 116.0, 117.4, 111.7,
87.9, 47.6, 42.2, 36.4, 30.1, 26.3; IR (KBr): ꢀ 3342, 3027, 2982,
1672, 1600, 1480, 1470, 1410, 686 cm-1; MS: m/z 826 (M+).
Anal. calcd. for C45H42N6O6S2: C, 65.36; H, 5.12; N, 10.16.
Found: C, 65.22; H, 5.10; N, 10.10.
4-[4-(2-Hydroxy-5-{4-hydroxy-3-[6-(4-nitrophenyl)-2-(3-oxo-
1-thia-4-azaspiro[4.5]dec-4-yl)-4-pyrimidinyl]benzyl}phenyl)-
6-(4-nitrophenyl)-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]decan-
4-[4-(2-Hydroxy-5-{4-hydroxy-3-[2-(3-oxo-1-thia-4-azaspiro-
[4.5]dec-4-yl)-6-(2-thienyl)-4-pyrimidinyl]benzyl}phenyl)-6-(2-
thienyl)-2-pyrimidinyl]-1-thia-4-azaspiro[4.5]decan-3-one (6h).
1
3-one (6c). Mp 169-71°C; Yield 78%; H NMR (DMSO-d6): ꢁ
10.40 (2H, s, OH), 8.20 (4H, d, J = 8.7 Hz, ArH), 8.00 (4H, d, J

Jul-Aug 2008
Synthesis of Methylene-bis-pyrimidinyl-spiro-4-thiazolidinones
1125
1
[14a] Chimirri, A.; Grasso, S.; Monforte, A. M.; Monforte, P.;
Zappala, M. Il Farmaco. 1991, 46, 817. b) Chimirri, A.; Grasso, S.;
Monforte, A. M.; Monforte, P.; Zappala, M. Il Farmaco. 1991, 46, 925.
c) Chimirri, A.; Grasso, S.; Molica, C.; Monforte, A. M.; Monforte, P.;
Zappala, M. Il Farmaco. 1996, 51, 279. d) Chimirri, A.; Grasso, S.;
Monforte, P.; Rao, A.; Zappala, M.; Monforte, A. M.; Pannecouque, C.;
Witvrouw, M.; Balzarini, J.; De Clercq, E. Antiviral Chem. Chemother.
1999, 10, 211. e) Rao, A.; Chimirri, A.; Stefania, F.; Monforte, A. M.;
Monforte, P.; Zappala, M. Arkivoc. 2004, 5, 147.
Mp 192-94°C; Yield 74%; H NMR (DMSO-d6): ꢀ 10.40 (2H, s,
OH), 8.21 (2H, s, ArH), 7.40-6.30 (12H, m, ArH), 4.10 (2H, s, CH2),
3.87 (4H, s, CH2), 2.10-1.50 (20H, m, CH2); 13C NMR (DMSO-d6): ꢀ
183.3, 175.5, 156.6, 152.4, 152.0, 146.0, 137.6, 134.7, 133.9, 132.3,
132.0, 123.4, 117.1, 115.2, 112.0, 87.0, 47.6, 42.3, 36.7, 30.5, 26.1;
IR (KBr): ꢀ 3345, 3062, 2985, 1680, 1595, 1480, 1472, 1410, 688
cm-1; MS: m/z 860 (M+). Anal. calcd. for C45H42N6O4S4: C, 62.91; H,
4.93; N, 9.79. Found: C, 62.88; H, 4.81; N, 9.67.
[15] Manro, M. R.; Monika, J.; Kaul, V. K. Pl. Dis. Res. 1997, 12,
70.
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