Synthesis of sulfur-containing heterocycles: Spiropyrimidinetriones, thioxopyrimidinediones, pyrazolidinediones, and isoxazolidinediones-Part II

Article abstract of DOI:10.1002/hc.1021

1-Aroyl-2-styrylsulfonylethene is the precursor for 4,4-dimethoxycarbonyl-2′,5-diaryl-3-(1′,3′-dioxolano)-1-thia-1 ,1-dioxide (4, which is the key intermediate for the synthesis of 7-aroyl-11-aryl-2,4-diazaspiro-[5,5]undecane-1,3,5-trione-9-thia-9,9-dioxi

Full text of DOI:10.1002/hc.1021

Heteroatom Chemistry
Volume 12, Number 3, 2001
Synthesis of Sulfur-Containing Heterocycles:
Spiropyrimidinetriones,
Thioxopyrimidinediones, Pyrazolidinediones,
and Isoxazolidinediones—Part II*
D. Bhaskar Reddy, N. Chandrasekhar Babu, and V. Padmavathi
Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, India
Received 24 June 1999; revised 14 November 2000
ones, pyrazolidinediones, and isoxazolidinediones
[1].
ABSTRACT: 1-Aroyl-2-styrylsulfonylethene is the
precursor for 4,4-dimethoxycarbonyl-2Ј,5-diaryl-3-
(1Ј,3Ј-dioxolano)-1-thia-1,1-dioxide (4), which is the
key intermediate for the synthesis of 7-aroyl-11-aryl-
2,4-diazaspiro[5,5]undecane-1,3,5-trione-9-thia-9,9-
dioxide(10)/3-thioxo-1,5-dione-9-thia-9,9-dioxide (11),
6-aroyl-10-aryl-2,3-diazaspiro[4,5]decane-1,4-dione-8-
thia-8,8-dioxide (12)/2-oxo-3-azaspiro [4,5]decane-1,4-
dione-8-thia-8,8-dioxide (13). The new compounds
were characterized by IR and H NMR spectral data.
᭧ 2001 John Wiley & Sons, Inc. Heteroatom Chem
12:131–135, 2001
RESULTS AND DISCUSSION
The key intermediates, 4,4-dimethoxycarbonyl-2Ј,5-
diaryl-3-(1Ј,3Ј-dioxolano)-1-thia-1,1-dioxides (4), for
the synthesis of the target molecules have been pre-
pared by the double Michael addition of dimethyl
malonate to 1-(2Ј-aryl-1Ј,3Ј-dioxolano)-2-styrylsul-
fonylethenes (3). When the same reaction was car-
ried out with 1-aroyl-2-styrylsulfonylethenes (1), an
open-chain product, 1-aroyl-5-aryl-6,6-dimethoxy-
carbonyl-3-thian-1-hexene-3,3-dioxide (2), was ob-
tained the structure of which was confirmed by IR
1
INTRODUCTION
1
(m, cmמ1) and H NMR (d, ppm) spectra. Absorption
Recent developments in our laboratory permitted
the elaboration of general methods for the synthesis
of asymmetric spiroheterocycles. A review of this
work, as well as our successful synthesis of sulfur-
containing spiro-heterocycles, prompted us to report
the present communication. Our synthetic studies in
this area have focused on exploiting the relationship
between Michael acceptors and Michael donors,
which has led to the development of sulfur contain-
ing spiropyrimidinetriones, thioxopyrimidinedi-
bands for olefinic (1604), carbonyl (1640 COAr, 1720
COOCH3), and sulfonyl groups (1340, 1120) were ob-
served. The H NMR spectrum indicates two dou-
1
blets and a quartet for methylene and methine pro-
tons apart from two doublets for two olefinic protons
at 2.24 (C6-H), 2.92 (C5-H), 3.95 (C4-H), 7.20 (C1-H),
and 7.94 (C2-H), and a sharp singlet for OCH3 at 3.90.
The cyclized product 4 was not obtained because
of the inertness of the olefinic bond toward Michael
addition, as it was flanked by two electron withdraw-
ing groups CO and SO2. However, the protection of
the carbonyl group in 1 by refluxing it with ethylene
glycol in benzene in the presence of p-tolunesulfonic
acid (p-TSA), followed by the reaction with dimethyl
malonate in the presence of Triton-B in benzene, fur-
Part I. Ref. [1].
Correspondence to: D. Bhaskar Reddy.
Contract Grant Sponsor: Council of Scientific and Industrial Re-
search (CSIR), New Delhi.
᭧ 2001 John Wiley & Sons, Inc.
131

132 Reddy, Babu, and Padmavathi
SCHEME 1
nished 4 in fairly good yield. The absence of the free
carbonyl absorption peak at 1682 and the presence
of carbonyl absorption peaks of carbomethoxy
groups in the region 1760 were observed in the IR
1
spectra. The H NMR spectrum showed two triplets
for methine protons at C3–H and at C5–H in the re-
gion 4.38 and 3.87, respectively. The methylene pro-
tons at C2 and C6 are magnetically nonequivalent.
The C2–Hax and C6–Hax showed signals at relatively
much downfield and as such merged with the signals
due to OCH3 of the carbomethoxy group and ap-
peared as a multiplet in the region 3.28–3.83. How-
ever, the C2–Heq and C6–Heq displayed double dou-
blets at two distinctly different regions, 2.68–2.74
and 2.91–2.98, respectively. The downfield absorp-
tion of C6–Heq may be due to an anisotropic effect of
the aryl moiety. The methylene protons of the diox-
olane ring displayed a multiplet at 3.62–3.69. The
two carbomethoxy groups showed two sharp singlets
at 3.58 and at 3.49. The splitting pattern thus sug-
gests that the two substituents in the thiandioxide
ring in its preferred rigid chair conformation adopt
a cis-1,3-diequatorial position [2]. (See Figure 1).
Compound 4 was made to react with urea, thio-
urea, hydrazine hydrate, and hydroxylamine hy-
drochloride to give 7-[2Јaryl-(1Ј-3Ј-dioxolano)]-11-
aryl-2,4-diazaspiro[5,5]-undacane-1,3,5-trione-9,9-
dioxides (6)/3-thioxo-1,5-dione-9-thia-9,9-dioxides
7 and 6-[2Јaryl(1Ј,3Ј-dioxolano)]10-aryl-2,3-diazas-
piro[4,5] decane-1,4-dione-8-thia-8,8-dioxides 8/2-
FIGURE 1
oxo-3-azaspiro[4,5]decane-1,4-di-one-8-thia-8,8-di-
oxides 9.
The absence of the carbonyl absorption band of
the carbomethoxy group around 1760 and the pres-
ence of NH stretching vibrations (3300–3475), car-
bonyl groups adjacent to the NH moiety (1665–1685)
in the IR confirmed their formation. A strong band
for the amidic carbonyl group (1690–1730) was ob-
served in 9. The 1H NMR spectra of these compounds
showed a different type of splitting pattern when
compared to 4. The C7–H, C11–H, and C8–H, C10–H in
6 and 7 and C6–H, C10–H, and C7–H, C9-H in 8 and 9
showed multiplets in the regions 4.65–4.84 and 3.45–
3.54, respectively. The signal due to the NH proton
was observed around 8.65–10.80, which disappeared
on deuteration. The splitting pattern and Drieding

Synthesis of Sulfur-Containing Heterocycles 133
SCHEME 2
model indicates that these compounds may adopt a
flexible conformation in order to minimize trans an-
nular interactions of the substituents with the thian-
dioxide moiety (See Figure 2).
methylene group of the 1,3-dioxolane moiety. How-
ever, in 10–13, the methine proton adjacent to the
aroyl moiety exhibited a double doublet at 5.26,
whereas the other methine proton adjacent to the
aryl group displayed a triplet at 4.32, which may be
due to the anisotropic effect of the carbonyl group.
A multiplet was observed for the methylene protons
in the region 3.50–3.58 in all the cases. However, the
preferred conformation of all these compounds, as
suggested by the spectra and Drieding model, is
found to be similar to those of 6–9.
Deprotection of the carbonyl group in 4 and 6–
9 was carried out by refluxing the compounds with
HCl in acetic acid in a 1:3 ratio, which selectively
hydrolyzed the 1,3-dioxolane ring to give 3-aroyl-5-
aryl-4,4-dimethoxycarbonyl-1-thian-1,1-dioxides (5)
and 7-aroyl-11-aryl-2,4-diazaspiro[5,5] undecane-
1,3,5-trione-9-thia-9,9-dioxides (10)/3-thioxo-1,5-di-
one-9-thia-9,9-dioxide (11) and 6-aroyl-10-aryl-2,3-
diazaspiro[4,5]-decane-1,4-dione-8-thia-8,8-dioxides
(12)/2-oxo-3-azaspiro[4,5]decane-1,4-dione-8-thia-8,
8-dioxides (13). In all these compounds, an absorp-
tion band due to a carbonyl group was observed
around 1680–1684, which indicates the presence of
EXPERIMENTAL
Melting points were determined on a Mel-Temp ap-
paratus and are uncorrected. IR spectra (KBr-disc)
were recorded on a Beckman IR-18 spectrophotom-
eter, 1H NMR spectra were recorded in (CDCl3/
DMSO-d6) with 300 MHz on a varian EM-360 spec-
1
an aroyl substituent. The H NMR spectrum of 5 is
the replica of 4, except for the signals due to the

134 Reddy, Babu, and Padmavathi
FIGURE 2
TABLE 1 Physical Data of Compounds 3–13
trophotometer using tetramethylsilane (TMS) as a
standard. Elemental analyses were obtained from
the University of Pune, Pune, India.
Com-
m.p.
(ЊC)
Yield
(%)
Com-
pound
m.p.
(ЊC)
Yield
(%)
pound
1-Aroyl-2-styrylsulfonylethenes (1)
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
150–152
159–160
149–151
198–200
205–207
189–191
208–210
211–213
207–209
210–212
210–212
207–209
208–209
214–215
217–219
221–223
231–233
228–230
80
83
88
68
77
74
80
79
83
70
74
75
69
76
72
66
69
68
9a
9b
9c
180–182
187–189
183–185
280–282
289–291
290–292
279–281
286–288
273–275
292–294
291–293
299–301
220–222
227–229
220–224
70
73
72
85
88
86
81
83
88
80
80
87
79
83
85
A solution of 1-aroyl-2-chloroethene [3] (5 mmol) in
methanol (20 mL) was added dropwise to sodium
styrylsulfinate [4] (5.5 mmol) in water (20 mL) with
stirring at 0–10ЊC for 3 hours. The crystallized solid
was filtered off, washed with water, dried, and re-
crystallized from methanol.
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
1-(2ЈAryl-1Ј3Јdioxolano)-2-styrylsulfonylethenes
(3)
A mixture of 1-aroyl-2-styrylsulfonylethene [5] (1
mmol), ethylene glycol (2 mmol), and p-toluenesul-
fonic acid (1 mmol) in benzene (40 mL) was refluxed
for 15 hours using a Dean-Stark apparatus. The re-
action mixture was poured into crushed ice and ex-
tracted with benzene, dried, and the solvent removed
by use of a rotary evaporator. The solid obtained was
recrystallized from methanol to give pure 3. The
physical data of these compounds are given in
Table 1.
Note: Satisfactory elemental analyses were obtained for 5, 10–13: C
ע 0.33; H ע 0.14; N ע 0.22.
2Ј11-Diaryl-7-(1Ј,3Ј-dioxolano)-2,4-
diazaspiro[5,5]undecane-1,3,5-trione-9-thia-9,9-
dioxides (6), 2Ј, 11-Diaryl-7-(1,3-dioxolano)-
2,4-diazaspiro[5,5]undecane-3-thioxo-1,5-
dione-9-thia-9,9-dioxides (7), 2Ј10-Diaryl-6-
(1Ј,3Ј-dioxolano)-2,3-diazaspiro[4,5]-decane-
1,4-dione-8-thia-8,8-dioxides (8), 2Ј,10-Diaryl-
6-(1,3-dioxolano)-2-oxo-3-azaspiro[4,5]
decane-1,4-dione-8-thia-8,8-dioxides (9)
4,4-Dimethoxycarbonyl-2Ј,3-diaryl-5-(1Ј3Ј-
dioxolano)-1-thia-1,1-dioxides (4)
A mixture of 3 (1.0 mmol) and dimethyl malonate
(1.5 mmol) was dissolved in benzene (10 mL) to
which a catalytic amount of Triton-B had been
added, and the mixture was refluxed for 3–4 hours.
The solvent was distilled off and the syrupy sub-
stance obtained was treated with methanol to pro-
vide a solid that was recrystallized from methanol.
The physical data of these compounds are presented
in Table 1.
A mixture of 4 (10 mmol), urea (10 mmol)/thiourea
(10 mmol)/50% hydrazine hydrate (15 mmol)/hy-
droxylamine hydrochloride (10 mmol), and 10 mL
of methanol was prepared. To this, 5 mL of 10% so-
dium methoxide was added, and the mixture was re-

Synthesis of Sulfur-Containing Heterocycles 135
fluxed for 8–12 hours. The progress of the reaction
was monitored by thin-layer chromatography. After
completion of the reaction, the contents were cooled
and poured on to crushed ice containing concen-
trated hydrochloric acid. The product obtained was
recrystallized from methanol to give 6–9, respec-
tively. The physical data of these compounds are
given in Table 1.
The physical data of these compounds are given in
Table 1.
REFERENCES
[1] Bhaskar Reddy, D.; Padmavathi, V.; Seenaiah, B.;
Padmaja, A. Heteroat Chem 1993, 4, (1), 55.
[2] (a) Bhaskar Reddy, D.; Padmavathi, V.; Muralidhar
Reddy, M. Indian J Chem 1992, 31B, 407, (b) Bhaskar
Reddy, D.; Padmavathi, V.; Reddy, S.; Ramana Reddy,
M. V. Sulfur Lett 1991, 13, 123, (c) Otto, H. H.; Ya-
mamura, Y. Arch Pharm 1975, 308, 768.
[3] Bhaskar Reddy, D.; Chandrasekhar Babu, N.; Pad-
mavathi, V.; Sumathi, R. P. Synthesis 1999, 3, 441.
[4] Bhaskar Reddy, D.; Ramana Reddy, P. V.; Vijaya-
lakshmi, S.; Ramana Reddy, M. V. Phosphorous Sul-
fur Silicon Relat Elem 1993, 84, 63.
[5] Bhaskar Reddy, D.; Chandrasekhar Babu, N.; Venu-
gopal Reddy, K.; Padmavathi, V. Indian J Chem (in
press).
Hydrolysis of 4 and 6–9
The hydrolysis was carried out by refluxing 4 and 6–
9 with HCl in AcOH (1:3 ratio) for 3–4 hours. The
reaction mixture was cooled and poured into
crushed ice. The solid obtained was filtered off and
recrystallized from methanol to give 5 and 10–13.